Iron-copper co-catalyzed process for carbon-carbon or carbon-heteroatom bonding

ABSTRACT

The present invention relates to a process for creating a Carbon-Carbon bond (C—C) or a Carbon-Heteroatom bond (C-HE) by reacting a compound carrying a leaving group with a nucleophilic compound carrying a carbon atom or a heteroatom (HE) that can substitute for the leaving group, creating a C—C or C-HE bond, wherein the reaction takes place in the presence of an effective quantity of a catalytic system comprising iron and copper.

The formation of C—N bond is one of the most important reactions innumerous syntheses of pharmaceutical and agrochemical compounds as wellas many commercial dye molecules. The copper-catalyzed Ullmann reaction(Ullmann F. and Kipper H., Ber. dtsch. Chem. Ges., 1095, 38, 2120-2126)has been the most used method in industry due to the attractive price ofcopper compared to other noble metals as palladium, ruthenium, etc.

Recently, Buchwald et al. (J. Am. Chem. Soc., 2001, 123, 7727-7729)proposed to use classical ligands for copper in order to achieve thiscopper-catalyzed reaction. PCT patent application WO-A-03/101966 by thepresent inventors describes new ligands of copper which allow realizingthe Ullmann type reaction in mild conditions and with catalytic amountof copper. These ligands are mostly copper-chelating oxime ligands whichrequire specific synthesis and consequently lead to final products withfairly higher costs.

Moreover, although copper is a less expensive and a less toxic materialas compared with palladium, nickel, ruthenium and the like, improvementsto catalysts as copper together with ligands as disclosed inWO-A-03/101966 are still to be done, especially regarding costs.

In recent years, some research groups have focused on iron-catalyzedcross-coupling reactions. Although some new scopes of iron catalyst havebeen achieved, the use of iron is always associated with the C—C bondformation employing magnesium reagent which limits its applications.

An objective of the present invention is to provide an efficientcatalytic system for cross-coupling reactions. Another objective is toprovide a simple and easily available catalytic system which isefficient for a wide variety of cross-coupling reactions, said catalyticsystem being less expensive and less toxic than the catalytic systemsknown in the art. Other objectives will be apparent in the followingspecification.

It has now been found that these objectives are met in whole or in partwith the subject of the present invention.

In a first aspect, the present invention relates to a process forcreating a Carbon-Carbon bond (C—C) or a Carbon-Heteroatom bond (C-HE)by reacting a compound carrying a leaving group with a nucleophiliccompound carrying a carbon atom or a heteroatom (HE) that can substitutefor the leaving group, creating a C—C or C-HE bond, wherein the reactiontakes place in the presence of an effective quantity of a catalyticsystem comprising iron and copper.

Applicants have now found that that the combined use of iron- andcopper-based compounds, as a catalytic system, allows cross-couplingreactions between a compound carrying a leaving group and a nucleophiliccompound, without it being necessary to use specific ligands or specificsolvents.

The general scheme of the process according to the present invention maybe illustrated as follows:

wherein:

-   -   Y—R⁰ represents a compound carrying a leaving group Y; and    -   R-Q: represents a nucleophilic compound, R being the residue of        said nucleophilic compound, and Q being a carbon atom or a        heteroatom (HE) that can substitute for said leaving group Y.

In one aspect of the process of the present invention, an arylationreaction is carried out by reacting an aromatic compound carrying aleaving group with a nucleophilic compound.

In another aspect of the process of the invention, a vinylation oralkynylation reaction is carried out by reacting a compound with adouble or triple bond in the α position to a leaving group respectively.Throughout the description of the present invention, the term“arylation” is used in its broad sense since it is envisaged that thecompound employed carries a leaving group which is either of theunsaturated aliphatic type, or of the carbocyclic aromatic orheterocyclic type.

The term “nucleophilic compound” means an organic hydrocarbon compoundthat may be acyclic or cyclic or polycyclic and comprises at least oneatom carrying a free electron pair, which may or may not carry a charge,preferably a nitrogen, oxygen, sulfur, boron or phosphorus atom, orcomprises a carbon atom that may donate its electron pair.

As mentioned above, the nucleophilic compound comprises at least oneatom carrying a free electron pair, which can be carried by a functionalgroup and/or a carbanion.

Examples of functional groups and/or carbanions comprising said atomthat can be mentioned are:

In a further aspect of the invention, the nucleophilic compoundcomprises at least one nitrogen atom carrying a free electron pairincluded in a saturated, unsaturated, or aromatic cycle; the cyclegenerally containing 3 to 8 atoms.

It should be noted that when the nucleophilic compound comprises afunctional group, examples of which are given above, and carries one ormore negative charges, said compound is then in its salt form. Thecounter-ion is generally a metallic cation such as an alkali metal,preferably potassium, sodium or lithium or an alkaline-earth metal,preferably calcium, or the residue of an organometallic compound such asmagnesium or zinc compound.

A first advantage of the process of the invention is that it is carriedout at moderate temperatures.

A further advantage is that a wide range of cross-coupling agents,especially arylation agents, for nucleophiles can be used, not onlyiodides, but also bromides, chlorides or triflates, especially aryliodides, but also aryl bromides, chlorides or triflates.

A still further advantage of the process of the invention is the use ofan iron/copper catalytic system rather than palladium or nickel, i.e. aless toxic catalyst, further bringing an additional economic advantage.

The process of the invention involves a large number of nucleophiliccompounds and examples are given below by way of illustration which arenot limiting in any way.

A first category of nucleophilic compounds to which the process of theinvention is applicable comprises organic nitrogen-containingderivatives, more particular primary or secondary amines; hydrazine orhydrazone derivatives; amides; sulfonamides; urea derivatives orheterocyclic derivatives, preferably nitrogen-containing and/orsulfur-containing.

More precisely, the primary or secondary amines can be represented bygeneral formula (Ia):

in which formula (Ia):R¹ and R², which may be identical or different, represent a hydrogenatom or a C₁-C₂₀ hydrocarbon group, which may be a saturated orunsaturated acyclic linear or branched aliphatic group; a saturated,unsaturated or aromatic, monocyclic or polycyclic carbocyclic orheterocyclic group; or a concatenation of said groups; and at most oneof the groups R¹ and R² represents hydrogen.

Preferred amines have formula (Ia) in which R¹ and R², which may beidentical or different, represent a C₁ to C₁₅ alkyl group, preferably C₁to C₁₀, a C₃ to C₈ cycloalkyl group, preferably C₅ or C₆, or a C₆ to C₁₂aryl or arylalkyl group.

More particular examples of groups R¹ and R² that can be mentioned areC₁ to C₄ alkyl groups, phenyl, naphthyl or benzyl groups.

More specific examples of amines with formula (Ia) that can be mentionedare aniline, N-methyl aniline, diphenylamine, benzylamine anddibenzylamine.

The present invention does not exclude the presence of one or moreinsaturations in the hydrocarbon chain(s), such as one or more doubleand/or triple bonds, which may or may not be conjugated.

The hydrocarbon chain(s) may also be interrupted by one or moreheteroatom(s) (e.g. oxygen, sulfur, nitrogen, phosphorous), and/or by anon-reactive functional group, such as for example —CO—.

It should be noted that the amino group can be in the form of anions. Insuch a case, the counter-ion is a metal cation, preferably an alkalimetal cation, more preferably sodium or potassium. Examples of suchcompounds that can be cited are sodium or potassium amide.

The hydrocarbon chain can optionally carry one or more substituents (forexample halogen, ester, amino or alkyl and/or arylphosphine) providedthat they do not interfere.

The linear or branched, saturated or unsaturated acyclic aliphatic groupcan optionally carry a cyclic substituent. The term “cycle” means asaturated, unsaturated or aromatic carbocyclic or heterocyclic cycle.

The acyclic aliphatic group can be connected to the cycle via a covalentbond, a heteroatom or a functional group such as oxy, carbonyl,carboxyl, sulfonyl, and the like.

Examples of cyclic substituents that can be envisaged arecycloaliphatic, aromatic or heterocyclic substituents, in particularcycloaliphatic substituents containing 6 carbon atoms in the cycle orbenzenic, said cyclic substituents themselves optionally carrying anysubstituent provided that they do not interfere with the reactionsoccurring in the process of the invention. Particular mention can bemade of C₁ to C₄ alkyl or alkoxy groups.

More particular aliphatic groups carrying a cyclic substituent includecycloalkylalkyl groups, for example cyclohexylalkyl, or arylalkylgroups, preferably C₇ to C₁₂, in particular benzyl or phenylethyl.

In the above formula (Ia), groups R¹ and R² may also independentlyrepresent a carbocyclic group that is saturated or contains 1 or 2unsaturated bonds in the cycle, generally C₃ to C₈, preferably with 6carbon atoms in the cycle; said cycle can be substituted. A preferredexample of this type of group that can be cited is cyclohexyl,optionally substituted with linear or branched alkyl groups containing 1to 4 carbon atoms.

R¹ and R² may independently represent an aromatic hydrocarbon group, inparticular a benzenic group of general formula (F₁):

in which:

-   -   t represents 0, 1, 2, 3, 4 or 5; and    -   W represents a group selected from linear or branched C₁-C₆        alkyl, linear or branched C₁-C₆ alkoxy, linear or branched C₁-C₆        alkylthio, —NO₂, —CN, halogen, or CF₃.

R¹ and R² may also independently represent a polycyclic aromatichydrocarbon group with cycles possibly forming between themortho-condensed or ortho- and peri-condensed systems. A more particularexample that can be cited is naphthyl; said cycle optionally beingsubstituted.

R¹ and R² can also independently represent a polycyclic hydrocarbongroup constituted by at least 2 saturated and/or unsaturated carbocyclesor by at least 2 carbocycles, only one of which being aromatic, andforming between them ortho- or ortho- and peri-condensed systems.Generally, the cycles are C₃ to C₈, preferably C₆. More particularexamples that can be cited are bornyl and tetrahydronaphthalene.

R¹ and R² can also independently represent a saturated, unsaturated oraromatic heterocyclic group, in particular containing 5 or 6 atoms inthe cycle, including one or two heteroatoms such as nitrogen atoms (notsubstituted with a hydrogen atom), sulfur or oxygen; the carbon atoms ofthis heterocycle may also be substituted.

R¹ and R² can also represent a polycyclic heterocyclic group defined aseither a group constituted by at least two aromatic or non aromaticheterocycles containing at least one heteroatom in each cycle, andforming ortho- or ortho- and peri-condensed systems between them, or agroup constituted by at least one aromatic or non aromatic hydrocarboncycle and at least one aromatic or non aromatic heterocycle formingbetween them ortho- or ortho- and peri-condensed systems; the carbonatoms of said cycles can optionally be substituted.

Examples of heterocyclic type groups R¹ and R² that can be cited includefuryl, thienyl, isoxazolyl, furazanyl, isothiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyranyl, phosphino and quinolyl,naphthyridinyl, benzopyranyl or benzofuranyl groups.

The number of substituents present on each cycle depends on the carboncondensation of the cycle and on the presence or otherwise of anunsaturated bond on the cycle. The maximum number of substituents thatcan be carried by a cycle can readily be determined by the skilledperson. Other nucleophilic compounds encompassed by the presentinvention may for example be hydrazine derivatives of formulae (Ib):

in which:

-   R³ and R⁴, which may be identical or different, have the meanings    given for R¹ and R² in formula (Ia), and at most one of the groups    R³ and R⁴ represents hydrogen.

More particularly, groups R³ and R⁴ represent a C₁ to C₁₅ alkyl group,preferably C₁ to C₁₀, a C₃ to C₈ cycloalkyl group, preferably C₅ or C₆,or a C₆ to C₁₂ aryl or aryl alkyl group. Still more particularly, R³ andR⁴ represent C₁ to C₄ alkyl, phenyl, benzyl or naphthyl.

Other nucleophiles comprise oximes and hydroxylamines, which may berepresented by general formulae (Ic) and (Id) respectively:

in which formulae:

-   -   R⁵ and R⁶, which may be identical or different, have the        meanings given for R¹ and R² in formula (Ia), and at most one of        the groups R³ and R⁴ represents hydrogen;    -   R⁷ has the meanings given for R¹ or R² in formula (Ia), except        hydrogen; and    -   R⁸ represents hydrogen, a linear or branched, saturated or        unsaturated acyclic aliphatic group, unsaturated or unsaturated,        monocyclic or polycyclic, carbocyclic group; or a concatenation        of said groups.

Preferred oximes or hydroxylamines are those of formulae (Ic) and (Id)respectively, wherein R⁵, R⁶ and R⁷ represent C₁ to C₁₅ alkyl,preferably C₁ to C₁₀; C₃ to C₈ cycloalkyl, preferably C₅ or C₆; or C₆ toC₁₂ aryl or arylalkyl.

As more particular examples of groups R⁵, R⁶ and R⁷, mention may be madeof C₁ to C₄ alkyl groups, phenyl, naphthyl or benzyl. Regarding R⁸, itpreferably represents C₁ to C₄ alkyl or benzyl.

According to another aspect, the present invention involves hydrazinetype nucleophilic compounds, which may be represented by the followingformula (Ie):

in which:

-   -   R⁹, R¹⁰ and R¹¹, which may be identical or different, have the        meanings given for R¹ and R² in formula (Ia);    -   R¹¹ represents hydrogen or a protective group G; and    -   at least one of the groups R⁹, R¹⁰ and R¹¹ does not represent        hydrogen;    -   or R⁹ and R¹⁰ may together form, with the nitrogen atom carrying        them, a saturated, unsaturated or aromatic, monocyclic or        polycyclic C₃-C₂₀ heterocyclic group.

Preferred hydrazines are of formula (Ie) above, wherein R⁹ and R¹⁰,which are the same or different, represent C₁-C₁₅ alkyl, preferablyC₁-C₁₀; C₃-C₈ cycloalkyl group, preferably C₅- or C₆; or C₆-C₁₂ aryl oraryl alkyl. Still preferred hydrazines are those of formula (Ie),wherein R⁹ and R¹⁰, which are the same or different, represent C₁ to C₄alkyl, phenyl, benzyl or naphthyl.

R⁹ and R¹⁰ may be linked together, so as to form, together with thenitrogen atom carrying them, a saturated, unsaturated or aromatic,monocyclic or polycyclic C₃-C₂₀ heterocyclic group, comprising two orthree ortho-condensed cycles, i.e. at least two cycles have two carbonatoms in common.

For polycyclic compounds, the number of atoms of each cycle may varypreferably between 3 and 6. According to a preferred embodiment, R⁹ andR¹⁰ together form cyclohexane or fluorenone.

In the above formula (Ie), R¹¹ preferably represents hydrogen, alkyl(preferably C₁-C₁₂), alkenyl or alkynyl (preferably C₂-C₁₂), cycloalkyl(preferably C₃-C₁₂), aryl or aryl alkyl (preferably C₆-C₁₂). Still morepreferably, R¹¹ represents hydrogen or C₁-C₄ alkyl.

It should be noted that when the nucleophilic compound comprises a NH₂group, the two hydrogen atom may react. In such a case, and in order toimprove the reaction selectivity, one or the two hydrogen atoms mayadvantageously be blocked, using a protective agent. Such protectiveagents are well known in the art, and mention may be made of commonlyused protective groups, such as for example acyl (acetyl, benzoyl), BOC(butyloxycarbonyl), CBZ (carbobenzoxy), FMOC(trifluoromethyloxycarbonyl) or MSOC (methanesulfenyl-2-ethoxycarbonyl).See e.g. Theodora W. Greene et al., Protective Groups in OrganicSynthesis, 2^(nd) edition, John Wiley & Sons, Inc., for the amino groupprotection and unprotection reactions.

Still other nucleophilic compounds that may be involved in the processof the present invention are hydrazone compounds, which may berepresented by formula (If):

in which:

-   -   R¹², R¹³ and R¹⁴, which may be identical or different, have the        meanings given for R¹ and R² in formula (Ia);    -   at most one of the groups R¹² and R¹³ represents hydrogen;    -   or R¹² and R¹³ may together form, with the carbon atom carrying        them, a saturated, unsaturated or aromatic, monocyclic or        polycyclic C₃-C₂₀ carbocyclic or heterocyclic group.

Preferred hydrazones are of formula (If) above, wherein R¹² and R¹³,which are the same or different, represent C₁-C₁₅ alkyl, preferablyC₁-C₁₀; C₃-C₈ cycloalkyl group, preferably C₅- or C₆; or C₆-C₁₂ aryl oraryl is alkyl. Still preferred hydrazones are those of formula (If),wherein R¹² and R¹³, which are the same or different, represent C₁ to C₄alkyl, phenyl, benzyl or naphthyl.

R¹² and R¹³ may be linked together, so as to form, together with thecarbon atom carrying them, a saturated, unsaturated or aromatic,monocyclic or polycyclic C₃-C₂₀ carbocyclic or heterocyclic group,comprising two or three ortho-condensed cycles.

For polycyclic compounds, the number of atoms of each cycle may varypreferably between 3 and 6. According to a preferred embodiment, R¹² andR¹³ together form cyclohexane or fluorenone.

In the above formula (If), R¹⁴ preferably represents hydrogen, alkyl(preferably C₁-C₁₂), alkenyl or alkynyl (preferably C₂-C₁₂), cycloalkyl(preferably C₃-C₁₂), aryl or aryl alkyl (preferably C₆-C₁₂). Still morepreferably, R¹¹⁴ represents hydrogen or C₁-C₄ alkyl.

The invention also encompasses amide type compounds, more particularlyof formula (Ig):R¹⁵—NH—CO—R¹⁶  (Ig)in which formula (Ig), R¹⁵ and R¹⁶ have the meanings given for R¹ and R²in formula (Ia).

Examples of compounds with formula (Ig) that can be cited areoxazolidine-2-one, benzamide and acetamide.

The invention is also applicable to sulfonamide type compounds, whichmay be for example of formula (Ih):R¹⁷—SO₂—NH—R¹⁸  (Ih)in which formula (Ih), R¹⁷ and R¹⁸ have the meanings given for R¹ and R²in formula (Ia).

An example of a compound with formula (Ih) comprises tosylhydrazide.

Other types of nucleophilic substrates that can be mentioned are ureaderivatives such as guanidines, which can be represented by formula Ii):

in which formula (II), groups R₁₉, which may be identical or different,have the meanings given for R₁ and R₂ in formula (Ia).

An example of a compound with formula (II) that can be cited isN,N,N′,N′-tetramethylguanidine.

Still further nucleophilic compounds that may be used in the process ofthe present invention comprise amino-acids and derivatives thereof, e.g.of following formula (Ij):

wherein

-   -   R_(AA) represents hydrogen or the residue of an amino acid,        preferably hydrogen; linear or branched C₁-C₁₂ alkyl optionally        carrying a functional group; C₆-C₁₂ aryl or aryl alkyl; or a        functional group, preferably a hydroxyl group;    -   R²⁰ and R²¹ have the meanings given for R¹ and R² in formula        (Ia);    -   R_(h) represents hydrogen; a metallic cation, preferably an        alkali metal cation; or a C₁-C₁₂ hydrocarbon group, preferably        C₁-C₁₂ alkyl.

In a preferred embodiment, R_(AA) in formula (Ij) above represents alkylpossibly carrying a functional group, e.g. —OH, —NH₂, —CO—NH₂, —NH—CNH—,—HN—C(O)—NH₂, —COOH, —SH, —S—CH₃, or an imidazole, pyrrole, or pyrazolegroup.

Examples of amino-acids include glycine, cysteine, aspartic acid,glutamic acid, histidine.

Nucleophilic compounds that are well suited to use in the process of theinvention are heterocyclic derivatives comprising at least onenucleophilic atom such as a nitrogen, sulfur or phosphorus atom.

More precisely, such compounds are of general formula (Ik):

in which formula (Ik):

-   -   A represents the residue of a cycle forming all or a portion of        a monocyclic or polycyclic, aromatic or non aromatic        heterocyclic system, wherein one of the carbon atoms is replaced        by at least one nucleophilic atom such as a nitrogen, sulfur or        phosphorus atom;    -   R²², which may be identical or different, represent substituents        on the cycle;    -   n represents the number of substituents on the cycle.

The invention is applicable to monocyclic heterocyclic compounds withformula (Ik) in which A represents a saturated or unsaturated oraromatic heterocycle in particular containing 5 or 6 atoms in the cycleand possibly containing 1 or 3 heteroatoms such as nitrogen, sulfur oroxygen, at least one of which is a nucleophilic atom, such as NH or S.

A can also represent a polycyclic heterocyclic compound defined as beingconstituted by at least 2 aromatic or non aromatic heterocyclescontaining at least one heteroatom in each cycle and forming ortho- orortho- and per-condensed systems between them, or a group constituted byat least one aromatic or non aromatic carbocycle and at least onearomatic or non aromatic heterocycle forming ortho- or ortho- andperi-condensed systems between them.

It is also possible to start from a substrate resulting from aconcatenation of a saturated, unsaturated or aromatic heterocycle asdescribed above and of a saturated, unsaturated or aromatic carbocycle.The term “carbocycle” preferably means a cycloaliphatic or aromaticcycle containing 3 to 8 carbon atoms, preferably 6.

It should be noted that the carbon atoms of the heterocycle canoptionally be substituted with groups R²², either completely orpartially.

The number of substituents present on the cycle depends on the number ofatoms in the cycle and on the presence or otherwise of unsaturated bondson the cycle. The maximum number of substituents that can be carried bythe cycle can readily be determined by the skilled person.

In formula (Ik), n is preferably 0, 1, 2, 3 or 4, preferably 0 or 1.

Examples of substituents are given below, but this list is not limitingin nature.

Group or groups R²², which may be identical or different, preferablyrepresent one of the following groups:

-   -   linear or branched C₁-C₆ alkyl, preferably C₁-C₄ alkyl, such as        methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or        tert-butyl;    -   linear or branched C₂-C₆, preferably C₂-C₄, alkenyl or alkynyl,        such as vinyl or allyl;    -   linear or branched C₁-C₆, preferably C₁-C₄, alkoxy or thioether,        such as methoxy, ethoxy, propoxy, isopropoxy or butoxy, or        alkenyloxy, preferably allyloxy or phenoxy;    -   cyclohexyl, phenyl or benzyl;    -   a group or function such as: hydroxyl, thiol, carboxyl, ester,        amide, formyl, acyl, aroyl, amide, urea, isocyanate,        thioisocyanate, nitrile, azide, nitro, sulfone, sulfonic,        halogen, pseudohalogen or trifluoromethyl.

The present invention is particularly applicable to compounds of formula(Ik) in which groups R²² more particularly represent alkyl or alkoxy.

More particularly, optionally substituted residue A represents one ofthe following cycles:

-   -   a monocyclic heterocycle containing one or more heteroatoms:

-   -   a bicycle comprising a carbocycle and a heterocycle comprising        one or more heteroatoms:

-   -   a tricycle comprising at least one carbocycle or a heterocycle        comprising one or more heteroatoms:

Preferred examples of heterocyclic compounds are those with formula (Ik)in which A represents a cycle such as: imidazole, pyrazole, triazole,pyrazine, oxadiazole, oxazole, tetrazole, indole, pyrrole, phthalazine,pyridazine or oxazolidine.

Among nucleophilic compounds that can also be used in the process of theinvention, mention may be made of alcohol or thiol type compoundsrepresented by the following formula (Im):R²³-Z  (Im)in which formula (Im):

-   -   R²³ represents a hydrocarbon group containing 1 to 20 atoms and        has the meanings given for R¹ or R² in formula (Ia);    -   Z represents a OM¹ or SM¹ type group, in which M¹ represents a        hydrogen atom or a metallic cation, preferably an alkali metal        cation.

Preferred compounds have formula (Im) in which R²³ represents ahydrocarbon group containing 1 to 20 carbon atoms, which may be a linearor branched, saturated or unsaturated acyclic aliphatic group; amonocyclic or polycyclic, saturated, unsaturated or aromatic carbocyclicor heterocyclic group; or a concatenation of said groups.

More precisely, R²³ preferably represents a linear or branched saturatedacyclic aliphatic group preferably containing 1 to 12 carbon atoms, morepreferably 1 to 4 carbon atoms.

The invention does not exclude the presence of unsaturation on thehydrocarbon chain, such as one or more double and/or triple bonds, whichmay or may not be conjugated.

As for R¹ in formula (Ia), the hydrocarbon chain may optionally beinterrupted by a heteroatom, a functional group, or may carry one ormore substituents.

In formula (Im), R²³ can also represent a saturated or non saturatedcarbocyclic group, preferably containing 5 or 6 carbon atoms in thecycle; a saturated or non saturated heterocyclic group, containing 5 or6 carbon atoms in the cycle including 1 or 2 heteroatoms such asnitrogen, sulfur, oxygen or phosphorus atoms; a monocyclic, aromaticheterocyclic or carbocyclic group, preferably phenyl, pyridyl, furyl,pyranyl, thiophenyl, thienyl, phospholyl, pyrazolyl, imidazolyl,pyrrolyl, or a polycyclic, aromatic heterocyclic or carbocyclic groupwhich may or may not be condensed, preferably naphthyl.

When R²³ includes a cycle, this may also be substituted. The nature ofthe substituent is of no importance, provided that it does not interferewith the principal reaction. The number of substituents is generally atmost 4 per cycle, usually 1 or 2. Reference should be made to thedefinition of R²² in formula (Ik).

The invention also encompasses the case in which R²³ comprises aconcatenation of aliphatic and/or cyclic, carbocyclic and/orheterocyclic groups.

One acyclic aliphatic group may be connected to a cycle via a covalentbond, a heteroatom or a functional group such as oxy, carbonyl, carboxy,sulfonyl, and the like.

More particular groups are cycloalkylalkyl, for example cyclohexylalkyl,or aralkyl groups containing 7 to 12 carbon atoms, in particular benzylor phenylethyl.

The invention also encompasses a concatenation of carbocyclic and/orheterocyclic groups, more particularly a concatenation of phenyl groupsseparated by a covalent bond or an atom or a functional group such as:oxygen, sulfur, sulfo, sulfonyl, carbonyl, carbonyloxy, imino,carbonylimino, hydrazo or alkylene (C₁-C₁₀, preferably C₁)-diimino.

The linear or branched, saturated or unsaturated acyclic aliphatic groupcan optionally carry a cyclic substituent. The term “cycle” means asaturated, unsaturated or aromatic carbocyclic or heterocyclic cycle.

Preferred compounds with formula (Im) have general formula (Im₁):

in which

-   -   D represents the residue of a monocyclic or polycyclic,        aromatic, carbocyclic group or a divalent group constituted by a        concatenation of two or more monocyclic aromatic carbocyclic        groups;    -   R²⁴ represents one or more substituents, which may be identical        or different;    -   Z represents an OM¹ or SM¹ group in which M1 represents a        hydrogen atom or a metallic cation, preferably an alkali metal        cation; and    -   n′ is 0, 1, 2, 3, 4 or 5.

Examples of substituents R²⁴ can be found by referring to those for R²²defined for formula (Ik).

More particular compounds with formula (Im₁) are those in which theresidue (D) represents:

-   -   a monocyclic or polycyclic aromatic carbocyclic group with        cycles that can together form an ortho-condensed system of        formula (F₁₁):

-   -   in which formula (F₁₁), m represents 0, 1 or 2 and symbols R²⁴        and n′, which may be identical or different, have the meanings        given above;    -   a group constituted by a concatenation of two or more monocyclic        aromatic carbocyclic groups with formula (F₁₂):

-   -   in which formula (F₁₂), symbols R²⁴ and n′, which may be        identical or different, have the meanings given above, p is 0,        1, 2 or 3 and W represents a covalent bond, a C₁-C₄ alkylene or        alkylidene, preferably a methylene group or isopropylidene        group, or a functional group such as oxy, carbonyl, carboxy,        sulfonyl, and the like.

Preferred compounds with formula (Im) have formulae (F₁₁) and (F₁₂) inwhich:

-   -   R²⁴ represents hydrogen, hydroxyl, —CHO, —NO₂, or a linear or        branched alkyl or alkoxy group containing 1 to 6 carbon atoms,        preferably 1 to 4 carbon atoms, more preferably methyl, ethyl,        methoxy or ethoxy;    -   W represents a covalent bond, alkylene or alkylidene containing        1 to 4 carbon atoms or an oxygen atom;    -   m is 0 or 1; n′ is 0, 1 or 2; p is 0 or 1.

Illustrative examples of compounds with formula (Im) that can inparticular be mentioned are:

-   -   those in which residue D has formula (F₁₁) in which m and n′        equal 0, such as phenol or thiophenol;    -   those in which residue D has formula (F₁₁) in which m equals 0        and n′ equals 1, such as hydroquinone, pyrocatechine, resorcin,        alkylphenols, alkylthiophenols, alkoxyphenols, salicylic        aldehyde, p-hydroxybenzaldehyde, methyl salicylate,        p-hydroxybenzoic acid methyl ester, chlorophenols, nitrophenols        or para-acetamidophenol;    -   those in which residue D has formula (F₁₁) in which m equals 0        and n′ equals 2, such as dialkylphenols, vanillin, isovanillin,        2-hydroxy-5-acetamido-benzaldehyde,        2-hydroxy-5-propionamidobenzaldehyde, 4-allyloxybenzaldehyde,        dichlorophenols, methylhydroquinone or chlorohydroquinone;    -   those in which residue D has formula (F₁₁) in which m equals 0        and n′ equals 3, such as 4-bromovanillin, 4-hydroxyvanillin,        trialkylphenols, 2,4,6-trinitrophenol,        2,6-dichloro-4-nitrophenol, trichlorophenols,        dichloro-hydroquinones or 3,5-dimethoxy-4-benzaldehyde;    -   those in which residue D has formula (F₁₁) in which m equals 1        and n′ is 1 or more, such as dihydroxynaphthalene,        4-methoxy-1-naphthol or 6-bromo-2-naphthol;    -   those in which residue D has formula (F₁₂) in which p is 1 and        n′ is 1 or more, such as 2-phenoxyphenol, 3-phenoxyphenol,        phenylhydroquinone, 4,4′-dihydroxybiphenyl, isopropylidene        4,4′-diphenol (bisphenol A), bis(4-hydroxyphenyl)methane,        bis(4-hydroxyphenyl)sulfone, bis(4-hydroxy-phenyl)sulfoxide,        tetrabromo bisphenol A.

As other nucleophilic compounds belonging to totally different familiesand that can be used in the process of the invention, mentioned may bemade of phosphorus-containing compounds and phosphorus- andnitrogen-containing compounds, more particularly those having thefollowing formulae:phosphides of formula (R²⁵)₂—P—  (In);phosphines of formula (R²⁵)₃—P  (Io);phosphonium azayidiides of formula (R²⁵)₃—P⁺—N²⁻  (Ip);phosphonium azaylides of formula (R²⁵)₃—P⁺—N⁻—R²⁶  (Iq);in which formulae (In) to (Iq), the R²⁵ groups, that may be identical ordifferent, and the R²⁶ group represent:

-   -   C₁-C₁₂ alkyl;    -   C₅-C₆ cycloalkyl;    -   C₅-C₆ cycloalkyl which is substituted by one or more C₁-C₄        alkyls or C₁-C₄ alkoxys;    -   phenylalkyl, the aliphatic part of which has from 1 to 6 carbon        atoms;    -   phenyl; or    -   phenyl substituted by one or more C₁-C₄ alkyls or C₁-C₄ alkoxys,        or by one or more halogen atoms.

As particularly preferred phosphorous-containing compounds, mention maybe made of tricyclohexylphosphine, trimethylphosphine,triethylphosphine, tri-n-butylphosphine, tri-iso-butylphosphine,tri-tert-butyl-phosphine, tribenzylphosphine,dicyclohexylphenylphosphine, triphenyl-phosphine,dimethylphenylphosphine, diethylphenylphosphine,di-tert-butyl-phenylphosphine.

Other nucleophilic compounds that can be used in the process of theinvention are hydrocarbon derivatives containing a nucleophilic carbon.

More particular examples are malonate type anions comprising a—OOC—HC⁻—COO— group.

Alkyl malonate anions with formula (Ir) can be mentioned:R²⁷—OOC—HC⁻(R²⁸)—COO—R′²⁷  (Ir)wherein:

-   -   R²⁷ and R′²⁷, which may be identical or different, represent        alkyl containing 1 to 12 atoms, preferably 1 to 4 atoms;    -   R²⁸ is chosen from among hydrogen; C₁-C₁₂ alkyl; C₅-C₆        cycloalkyl; C₅-C₆ cycloalkyl, substituted with one or more C₁-C₄        alkyls, or C₁-C₄ alkoxys; phenyl; phenyl substituted with one or        more C₁-C₄ alkyls, or C₁-C₄ alkoxys or with one or more halogen        atoms; phenylalkyl, the aliphatic portion of which containing 1        to 6 carbon atoms.

It is also possible to cite malonitrile and malodinitrile type anionscontaining a R²⁷—OOC—HC⁻ (R²⁸)—CN or NC—HC⁻—CN group respectively, inwhich R²⁷ and R²⁸ have the meanings given above.

It is also possible to use nitrile type compounds containing a R′²⁸—CNgroup, wherein R′²⁸ has any nature and particularly has the meaningsgiven for R¹ in formula (Ia) and may also represent a metallic cation,preferably an alkali cation, more preferably lithium, sodium orpotassium.

Examples of nitrites that can be mentioned are acetonitrile,cyanobenzene, optionally carrying one or more substituents on thebenzene ring, or ethanal cyanhydrine CH₃CH(OH)CN.

It is also possible to use acetylenide type compounds in the process ofthe invention, which may represented by the formula (Is):R²⁹—C≡C⁻  (Is)in which formula R²⁹ is of any nature and particularly has the meaningsgiven for R¹ in formula (Ia); the counter-ion is a metal cation,preferably sodium or potassium.

Particular examples that can be cited are sodium or potassium acetylideor diacetylide.

Other classes of nucleophilic compounds that can be employed in theprocess of the invention are profene type compounds and theirderivatives represented by the following formula:R³⁰—HC⁻—COO—R³¹  (It)in which formula:

-   -   R³⁰ has the meanings given for R1 in formula (Ia); and    -   R³¹ represents alkyl containing 1 to 12 atoms, preferably 1 to 4        atoms.

Preferred compounds are those with formula (It) in which R³⁰ representsalkyl containing 1 to 12 carbon atoms, cycloalkyl containing 5 or 6carbon atoms and aryl containing 6 or 12 carbon atoms or anitrogen-containing heterocycle containing 5 or 6 atoms.

Nucleophilic compounds that can also be mentioned are those comprising acarbanion, the counter-ion of which is a metal and which have thefollowing formulae:

in which:

-   -   R³² represents:        -   alkyl containing 1 to 12 carbon atoms;        -   cycloalkyl containing 5 or 6 carbon atoms;        -   cycloalkyl containing 5 or 6 carbon atoms, substituted with            one or more alkyl radicals containing 1 to 4 carbon atoms or            alkoxy radicals containing 1 or 4 carbon atoms;        -   phenylalkyl, the aliphatic portion of which containing 1 to            6 carbon atoms;        -   phenyl;        -   phenyl substituted with one or more alkyl radicals            containing 1 to 4 carbon atoms or alkoxy radicals containing            1 to 4 carbon atoms or with one or more halogen atoms; or        -   a saturated, unsaturated or aromatic heterocyclic group,            preferably comprising 5 or 6 atoms, the heteroatom being            sulfur, oxygen or nitrogen;    -   R′³² and R″³² represent hydrogen or a group such as R³²;    -   two of groups R³², R′³² and R″³² may be connected together to        form a carbocycle or a saturated, unsaturated or aromatic        heterocycle preferably containing 5 or 6 carbon atoms;    -   M₂ represents a metallic element from group (IA) of the periodic        table;    -   M₃ represents a metallic element from groups (IIA) and (IIB) of        the periodic table;    -   X₁ represents chlorine or bromine;    -   v is the valency of metal M₃; and    -   w is 0 or 1.

In the present specification, reference is made to the periodic tablepublished in “Bulletin de la Société Chimique de France”, no. 1 (1966).

Preferred compounds with formula (Iu₁) to (Iu₃) include those in whichthe metals are lithium, sodium, magnesium or zinc and X₁ representschlorine.

According to an advantageous feature, R³², R′³² and R″³² represent C₁-C₄alkyl, cyclohexyl or phenyl; or said groups may form a benzene orpyridine or thiophene cycle.

As examples, mention may be made of n-butyllithium, t-butyllithium,phenyllithium, methyl- or ethyl- or phenyl-magnesium bromide orchloride, diphenylmagnesium, dimethyl- or diethyl-zinc,cyclo-pentadienezinc, and ethyl zinc chloride or bromide.

Still other nucleophilic compounds that can be used in the process ofthe present invention include boronic acids or their derivatives, moreparticularly those with the following formula (Iv):

in which:

-   -   R³³ represents a monocyclic or polycyclic, aromatic, carbocyclic        or heterocyclic group;    -   T¹ and T², which may be identical or different, represent        hydrogen, linear or branched, saturated or unsaturated aliphatic        group containing from 1 to 20 carbon atoms, or a R³³ group.

More precisely, the boronic acid or derivative has formula (Iv) in whichR³³ represents an aromatic carbocyclic or heterocylic group. R³³ canhave the meanings given above for D in formula (Im₁). However, R³³ moreparticularly represents a carbocyclic group such as a phenyl, naphthylor heterocyclic group such as a pyrrolyl, pyridyl, pyrimidyl,pyridazinyl, pyrazinyl, 1,3-thiazolyl, 1,3,4-thiadiazolyl or thienyl.

The aromatic cycle can also be substituted. The number of substituentsis generally at most 4 per cycle, but usually it is 1 or 2. Referenceshould be made to the definition of R²² in formula (Ik) for examples ofsubstituents.

Preferred substituents are alkyl or alkoxy groups containing 1 to 4carbon atoms, amino, nitro, cyano, halogen or trifluoromethyl.

T¹ and T², which may be identical or different, more particularlyrepresent hydrogen, or a linear or branched acyclic aliphatic groupcontaining from 1 to 20 carbon atoms which may be saturated or containone or more unsaturated bonds (i.e. double and/or triple bond(s)) in thechain, preferably 1 to 3 unsaturated bonds, preferably simple orconjugated double bonds.

T¹ and T², preferably represent an alkyl group containing from 1 to 10carbon atoms, preferably 1 to 4, or an alkenyl group containing from 2to 10 carbon atoms, preferably vinyl or 1-methylvinyl.

Additionally, T¹ and T² can have the meanings given for R₂₆; inparticular, any cycle can also carry a substituent as described above.

Preferably, R³³ represents a phenyl group.

The scope of the present invention encompasses derivatives of boronicacids such as anhydrides and esters, more particularly alkyl esterscontaining 1 to 4 carbon atoms.

Particular examples of arylboronic acids that can be cited are:benzeneboronic acid, 2-thiopheneboronic acid; 3-thiopheneboronic acid;4-methylbenzeneboronic acid, 3-methylthiophene-2-boronic acid,3-amino-benzeneboronic acid, 3-aminobenzeneboronic acid hemisulfate,3-fluoro-benzeneboronic acid, 4-fluorobenzeneboronic acid,2-formylbenzeneboronic acid, 3-formylbenzeneboronic acid,4-formylbenzeneboronic acid, 2-methoxy-benzeneboronic acid,3-methoxybenzeneboronic acid, 4-methoxybenzene-boronic acid,4-chlorobenzeneboronic acid, 5-chlorothiophene-2-boronic acid,benzo[b]furan-2-boronic acid, 4-carboxybenzeneboronic acid,2,4,6-trimethyl-benzeneboronic acid, 3-nitrobenzeneboronic acid,4-(methylthio)benzene-boronic acid, 1-naphthaleneboronic acid,2-naphthaleneboronic acid, 2-methoxy-1-naphthaleneboronic acid,3-chloro-4-fluorobenzeneboronic acid, 3-acetamidobenzeneboronic acid,3-trifluoromethylbenzeneboronic acid, 4-trifluoromethylbenzeneboronicacid, 2,4-dichlorobenzeneboronic acid, 3,5-dichlorobenzeneboronic acid,3,5-bis-(trifluoromethyl)benzeneboronic acid, 4,4′-biphenyldiboronicacid, and esters and anhydrides of said acids.

The present text provides lists of nucleophilic compounds that are in noway limiting and any type of nucleophilic compound can be envisaged.

As stated above and in accordance with the process of the presentinvention, a —C—C or —C-HE- (wherein HE is O, S, P, N, Si, B, and thelike) bond can be created by reacting a nucleophilic compound, such asthose described herein before, with a compound carrying a leaving group,typically a compound comprising one unsaturated bond in the position αto a leaving group.

More precisely, the compound carrying a leaving group is represented bygeneral formula (II):Y—R⁰  (II)in which formula R⁰ represents a hydrocarbon group containing from 2 to20 carbon atoms and optionally has at least one unsaturation (a doubleor a triple bond) in the position α to a leaving group Y, or representsa monocyclic or polycyclic, aromatic, carbocyclic and/or heterocyclicgroup.

In accordance with the process of the invention, the compound of formula(I) is reacted with a compound of formula (II) in which:

-   -   R⁰ represents an aliphatic hydrocarbon group optionally        containing at least one double bond and/or one triple bond in        the position α to the leaving group or a cyclic hydrocarbon        group containing an unsaturated bond carrying a leaving group;        or    -   R⁰ represents a monocyclic or polycyclic, aromatic, carbocyclic        and/or heterocyclic group;    -   Y represents a leaving group, preferably halogen or a sulfonic        ester group of formula —OSO₂—R^(e), in which R^(e) is a        hydrocarbon group.

The compound of formula (II) will henceforth be designated as the“compound carrying a leaving group”.

In the formula for the sulfonic ester group, R^(e) is a hydrocarbongroup of any nature. However, given that Y is a leaving group, it isadvantageous from an economic viewpoint for R^(e) to be simple innature, and more particularly to represent a linear or branched alkylgroup containing from 1 to 4 carbon atoms, preferably methyl or ethyl,but it can also represent phenyl or tolyl or trifluoromethyl, forexample.

Preferred group Y is a triflate group, which corresponds to a groupR^(e) representing trifluoromethyl.

Bromine or chlorine atoms constitute preferred leaving groups.

More particularly, compounds of formula (II) used in accordance with theprocess of the present invention can be classified into three groups:

-   (1) aliphatic type compounds, carrying a double bond which can be    represented by formula (IIa):

in which formula (IIa):

-   -   R³⁴, R³⁵ and R³⁶, which may be identical or different, represent        hydrogen or a hydrocarbon group containing 1 to 20 carbon atoms,        which can be a linear or branched, saturated or unsaturated        aliphatic group; a monocyclic or polycyclic, saturated,        unsaturated or aromatic carbocyclic or heterocyclic group; or a        concatenation of aliphatic and/or carbocyclic and/or        heterocyclic groups as defined above;    -   Y represents the leaving group, as defined above;

-   (2) aliphatic type compounds, carrying a triple bond which can be    represented by formula (IIb):    R³⁴—C≡C—Y  (IIb)    in which formula (IIb):    -   R³⁴ has the same definition as the one given for formula (IIa);        and    -   Y represents the leaving group, as defined above;

-   (3) aromatic type compounds, hereinafter designated as “haloaromatic    compound” and which can be represented by formula (IIc):

in which formula (IIc):

-   -   E represents the residue of a cycle forming all or a portion of        a monocyclic or polycyclic, aromatic, carbocyclic and/or        heterocyclic system;    -   R³⁷, which may be identical or different, represents        substituents on the cycle;    -   Y represents a leaving group as defined above; and    -   n″ represents the number of substituents on the cycle.

The invention is applicable to unsaturated compounds of formula (IIa) orof formula (IIb) in which R³⁴ preferably represents a saturated linearor branched acyclic aliphatic group, preferably containing from 1 to 12carbon atoms.

The invention does not exclude the presence of a further unsaturatedbond on the hydrocarbon chain, such as a triple bond or one or moredouble bonds, which may or may not be conjugated.

The hydrocarbon chain can optionally be interrupted with a heteroatom(for example oxygen or sulfur) or by a functional group, provided thatit does not react; in particular, a group such as —CO— can be cited.

The hydrocarbon chain can optionally carry one or more substituentsprovided that they do not react under the reaction conditions;particular mention can be made of halogen, nitrile or trifluoromethyl.

The linear or branched, saturated or unsaturated acyclic aliphatic groupcan optionally carry a cyclic substituent. The term “cycle” means asaturated, unsaturated or aromatic, carbocyclic or heterocyclic cycle.

The acyclic aliphatic group can be connected to the cycle via a covalentbond, a heteroatom or a functional group such as oxy, carbonyl, carboxy,sulfonyl, and the like.

Examples of cyclic substituents that may be mentioned arecycloaliphatic, aromatic or heterocyclic substituents, in particularcycloaliphatic containing 6 carbon atoms in the cycle, or benzenicsubstituents, said cyclic substituents themselves optionally carryingany substituent provided that these do not interfere with the reactionsoccurring in the process of the invention. Particular mention can bemade of alkyl or alkoxy groups containing from 1 to 4 carbon atoms.

More particular examples of aliphatic groups carrying a cyclicsubstituent are aralkyl groups containing 7 to 12 carbon atoms, inparticular benzyl or phenylethyl.

In formulae (IIa) and/or (IIb), R³⁴ can also represent a carbocyclicgroup that may or may not be saturated, preferably containing 5 or 6carbon atoms in the cycle, preferably cyclohexyl; a heterocyclic group,which may or may not be saturated, in particular containing 5 or 6carbon atoms in the cycle 1 or 2 of which are heteroatoms such asnitrogen, sulfur or oxygen; a monocyclic aromatic carbocyclic group,preferably phenyl, or a polycyclic aromatic carbocyclic group, which mayor may not be condensed, preferably naphthyl.

Regarding R³⁵ and R³⁶, they preferably represent hydrogen or alkylcontaining from 1 to 12 carbon atoms, or phenyl or aralkyl groupcontaining from 7 to 12 carbon atoms, preferably benzyl.

In formulae (IIa) and/or (IIb), R³⁴, R³⁵ and R³⁶ more particularlyrepresent hydrogen or else R³⁴ represents phenyl and R³⁵ and R³⁶represent hydrogen.

It should be noted that R³⁴ and R³⁵ may also represent a functionalgroup, provided that it does not interfere within the coupling reaction.As examples, mention may be made of functional groups such as amido,ester, ether, cyano.

Examples of compounds of formulae (IIIa) and (IIb) include vinylchloride or bromide, β-bromo- or β-chloro-styrene, or bromoalkyne oriodoalkyne.

The invention is of particular application to haloaromatic compounds offormula (IIc) in which E is the residue of a cyclic compound, preferablycontaining at least 4 carbon atoms in its cycle, preferably 5 or 6,optionally substituted, and representing at least one of the followingcycles:

-   -   a monocyclic or polycyclic aromatic carbocycle, i.e., a compound        constituted by at least 2 aromatic carbocycles and between them        forming ortho- or ortho- and peri-condensed systems, or a        compound constituted by at least 2 carbocycles, only one of        which is aromatic and between them forming ortho- or ortho- and        peri-condensed systems;    -   a monocyclic aromatic heterocycle containing at least one of        heteroatoms P, O, N or S or a polycyclic aromatic heterocycle,        i.e., a compound constituted by at least 2 heterocycles        containing at least one heteroatom in each cycle wherein at        least one of the two cycles is aromatic and between them forming        ortho- or ortho- and peri-condensed systems, or a compound        constituted by at least one carbocycle and at least one        heterocycle at least one of the cycles being aromatic and        forming between them ortho- or ortho- and peri-condensed        systems.

More particularly, optionally substituted residue E preferablyrepresents the residue of an aromatic carbocycle such as benzene, anaromatic bicycle containing two aromatic carbocycles such asnaphthalene; or a partially aromatic bicycle containing two carbocyclesone of which is aromatic, such as tetrahydro-1,2,3,4-naphthalene.

The invention also envisages the fact that E can represent the residueof a heterocycle provided that it is more electrophilic than compound offormula (Ik).

Particular examples that can be cited are aromatic heterocycle such asfuran or pyridine; aromatic bicycle comprising an aromatic carbocycleand an aromatic heterocycle such as benzofuran or benzopyridine;partially aromatic bicycle comprising an aromatic carbocycle and aheterocycle such as methylenedioxybenzene; aromatic bicycle comprisingtwo aromatic heterocycles such as 1,8-naphthylpyridine; partiallyaromatic bicycle comprising a carbocycle and an aromatic heterocyclesuch as 5,6,7,8-tetrahydroquinoline.

In the process of the invention, a haloaromatic compound of formula(IIc) is preferably used, in which E represents an aromatic nucleus,preferably benzene or naphthalene.

The aromatic compound of formula (IIc) can carry one or moresubstituents.

In the present specification, the term “one or more” generally meansless than 4 substituents R³⁷ on the aromatic nucleus. Reference shouldbe made to the definitions of R²², in formula (Ik) for various examplesof substituents.

R³⁷ may also represent a saturated, unsaturated or aromatic heterocyclecomprising 5 or 6 atoms and comprising sulfur, oxygen or nitrogen as theheteroatom. Pyrazolyl or imidazolyl groups can be typically cited inthis respect.

In formula (IIc), n″ is 0, 1, 2, 3 or 4, preferably 1 or 2.

Examples of compounds of formula (IIc) include p-chlorotoluene,p-bromoanisole and p-bromotrifluorobenzene.

The quantity of compound carrying a leaving group of formula (II),preferably of either formula (IIa), (IIb) or (IIc), is generallyexpressed with respect to the quantity of nucleophilic compound and mayvary in great proportions, advantageously is close to stoichiometry. Theratio between the number of moles of compound carrying a leaving groupand the number of moles of nucleophilic compound is usually in the range0.1 to 2.0, preferably in the range 0.5 and 1.5, more preferably in therange 0.8 and 1.2, for example in the range 0.9 and 1.1.

In accordance with the process of the invention, the nucleophiliccompound, preferably of formulae (Ia) to (Iv), is reacted with acompound carrying a leaving group, preferably of formula (II), morepreferably of formula (IIa), (IIb) or (IIc), in the presence of aneffective quantity of an iron/copper catalytic system.

It has indeed now been found that it is possible to achievecross-coupling reactions between nucleophilic compounds and compoundscarrying a leaving group, using an iron-based catalyst, in associationwith a copper-based catalyst.

Iron-based catalysts to be used in the present invention are knowncompounds.

As examples of iron-based catalysts useful in the present invention,mention may be made of, among others, metallic iron, oxides of iron(II)or iron(III), hydroxides of iron(II) or iron(III), organic or inorganicsalts of iron(II) or iron(III) and iron(II) or iron(III) complexes withcommon usual ligands.

Preferred examples of iron-based catalysts include, but are not limitedto, iron(0), As examples of iron-based catalysts useful in the presentinvention, mention may be made of, among others, iron(0), iron halides(ex: iron(II) iodide, iron(II) bromide, iron(III) bromide, iron(II)chloride, iron(III) chloride, iron(II) fluoride, iron(III) fluoride),iron oxides or hydroxides (ex: iron(II) oxide, iron(III) oxide,iron(III) hydroxide), iron nitrates (ex: iron(II) nitrate, iron(III)nitrate), iron sulfates, sulfides or sulfites (ex: iron(II) sulfate,iron(III) sulfate, iron(II) sulfite, iron sulfide, iron disulfide), ironphosphates (ex: iron(III) phosphate), iron perchlorates (ex: iron(III)perchlorate) or iron organic salts in which the counter anion involvesat least one carbon atom (ex: iron(II) acetate, iron(III) acetate,iron(III) trifluoromethylsulfonate, iron(II) methylate, iron(III)methylate, iron(III) acetylacetonate).

Mixtures of two or more iron-based catalysts may also be used. Preferrediron-based catalysts are organic or inorganic salts of iron(III), morepreferably iron(III) chloride, iron(III) acetate, iron(III)acetylacetonate

[Fe(acac)₃].

Similarly, copper-based catalysts are known compounds and are effectivein the process of the invention, when used in association with theabove-mentioned iron-based catalyst.

Examples of copper-based catalysts, mention may be made of, amongothers, metallic copper, oxides of copper(I) or copper(II), hydroxidesof copper(I) or copper(II), organic or inorganic salts of copper(I) orcopper(II) and copper(I) or copper(II) complexes with common usualligands.

Preferred examples of copper-based catalysts include, but are notlimited to, copper(0), copper halides (ex: copper(I) iodide, copper(I)bromide, copper(II) bromide, copper(I) chloride, copper(II) chloride),copper oxides or hydroxides (ex: copper(I) oxide, copper(II) oxide,copper(II) hydroxide), copper nitrates (ex: copper(I) nitrate,copper(II) nitrate), copper sulfates or sulfites (ex: copper(I) sulfate,copper(II) sulfate, copper(I) sulfite), copper organic salts in whichthe counter anion involves at least one carbon atom (ex: copper(II)carbonate, copper(I) acetate, copper(II) acetate, copper(II)trifluoromethylsulfonate, copper(I) methylate, copper(II) methylate,copper(II) acetylacetonate).

Mixtures of two or more copper-based catalysts may also be used.Preferred copper-based catalysts are copper(0) (Cu), copper(I) iodide(CuI), copper(II) oxide (CuO), copper(II) acetylacetonate [Cu(acac)₂],CuI+Cu(acac)₂.

The iron-based catalyst/copper-based catalyst molar ratio (expressed as[number of moles of Fe/number of moles of Cu]) is generally in the range10/1 to 1/10. Preferably, for economical and toxicological reasons, theratio is in the range 10/1 to 1/1, more preferably 5/1 to 1/1, forexample about 3/1.

Associations of any of iron-based catalysts with any of copper-basedcatalysts are suitable for the process of the present invention,preferably associations of any of the above-listed iron-based catalystswith any of the above-listed copper-based catalysts. According to apreferred embodiment, the process of the invention uses a catalyticsystem comprising iron, preferably organic or inorganic salts ofiron(III), more preferably iron(III) chloride, iron(III) acetate and/oriron(III) acetylacetonate [Fe(acac)₃], or mixtures thereof, togetherwith a catalyst selected from Cu(0), CuI, CuO, Cu(acac)₂, and mixturesthereof, e.g. CuI+Cu(acac)₂

The total amount of catalyst ([Fe]+[Cu]) involved in the process of thepresent invention, expressed as the molar ratio between (number of molesof Fe+number of moles of Cu) and the number of moles of the compoundcarrying a leaving group, is generally in the range 0.001 to 0.5,preferably 0.01 to 0.1.

A base, the function of which is to trap the leaving group, is also usedin the process of the invention.

Bases suitable for the process according to the invention may becharacterized by their pKa greater than about 2, preferably in the rangeof 4 to 30.

The pKa is defined as the ionic dissociation constant of the acid/basepair when water is used as the solvent. Reference should be made, interalia, to the “Handbook of Chemistry and Physics”, 66^(th) edition, p.D-161 and D-162, in order to select a base with a suitable pKa.

Suitable bases that can be cited include mineral bases such as alkalimetal carbonates, bicarbonates, phosphates or hydroxides, preferably ofsodium, potassium, caesium or alkaline-earth metals, preferably calcium,barium or magnesium.

It is also possible to use alkali metal hydrides, preferably sodiumhydride or alkali metal alcoholates, preferably of sodium or potassium,more preferably sodium methylate, ethylate or tertiobutylate.

It is also possible to use organic bases such as tertiary amines, moreparticularly triethylamine, tri-n-propylamine, tri-n-butylamine, methyldibutylamine, methyl dicyclohexylamine, ethyl diisopropylamine,N,N-diethyl cyclohexylamine, pyridine, dimethylamino-4-pyridine,N-methyl piperidine, N-ethyl piperidine, N-n-butyl piperidine,1,2-methylpiperidine, N-methyl pyrrolidine and 1,2-dimethylpyrrolidine.

Preferred bases are alkali metal carbonates.

The quantity of base employed is such that the ratio between the numberof moles of base and the number of moles of aromatic compound carryingthe leaving group is preferably in the range 1 to 4.

Where the compound carrying the leaving group may appear not is to bereactive enough, it may be useful to add to the reaction mixture aniodide compound, for example of formula MI, wherein M is an alkali metalor an earth-alkali metal, preferably chosen from among lithium, sodiumor potassium, preferably NaI is used. The amount of iodide compound thatmay be used in the reaction may vary in great proportions and isgenerally equal to, or about the same as, half the amount of compoundcarrying the leaving group, expressed in moles.

The use of said iodide compound is for example useful, advantageouslywhere the compound carrying the leaving group is an aryl bromide, inorder to enable the reaction to occur and/or to enable the reaction tobe run at lower temperatures and/or improve the yield of the reaction.

The process of the invention is usually carried out in the presence ofan organic solvent or mixtures of organic solvents. Convenient solventsare those that do not react under the reaction conditions.

Preferably, the solvents to be used in the process of the presentinvention are polar organic solvents, more preferably aprotic polarorganic solvents.

Solvents that may be used in the process of the present invention are,as non limiting examples, chosen from among:

-   -   linear or cyclic carboxamides, such as N,N-dimethylacetamide        (DMAC), N,N-diethylacetamide, dimethylformamide (DMF),        diethylformamide or 1-methyl-2-pyrrolidinone (NMP);    -   dimethylsulfoxide (DMSO);    -   hexamethylphosphotriamide (HMPT);    -   tetramethyurea;    -   nitro compounds such as nitromethane, nitroethane,        1-nitropropane, 2    -   nitropropane or mixtures thereof, and nitrobenzene;    -   aliphatic or aromatic nitriles such as acetonitrile,        propionitrile, butanenitrile, isobutanenitrile, pentanenitrile,        2-methylglutaronitrile or adiponitrile;    -   tetramethylene sulfone (sulfolane);    -   organic carbonates such as dimethylcarbonate,        diisopropylcarbonate or di-n-butylcarbonate;    -   alkyl esters such as ethyl or isopropyl acetate;    -   halogenated or non halogenated aromatic hydrocarbons such as        chlorobenzene or toluene;    -   ketones, such as acetone, methylethylketone,        methylisobutylketone, cyclopentanone, cyclohexanone;    -   nitrogen-containing heterocycles such as pyridine, picoline and        quinolines.

As stated above, it is also possible to use a mixture of solvents.Preferred solvents are carboxamides, such as DMF, acetonitrile, DMSO,NMP, DMAC.

The quantity of organic solvent to be used is depending on the nature ofthe selected organic solvent. Said quantity is determined so that theconcentration of the compound carrying a leaving group in the organicsolvent is preferably in the range 5% to 40% by weight.

According to an embodiment, the nucleophilic compound and/or thecompound carrying the leaving group may be used as solvent(s) of thereaction.

The formation of the C—C or C-HE bond according to the process of theinvention is generally conducted at a temperature that is advantageouslyin the range 0° C. to 200° C., preferably in the range 20° C. to 170°C., more preferably in the range 25° C. to 140° C.

The reaction is generally carried out at atmospheric pressure, but mayalso be run at higher pressures of up to 10 bars, for example.

In practice, the reaction is simple to carry out.

The order of introducing using the reagents in the reaction medium isnot critical. Usually, the catalytic system, the nucleophilic compound,preferably of formulae (Ia) to (Iv), the base, the compound carrying aleaving group, preferably of formula (II), more preferably of formula(IIa), (IIb) or (IIc), optionally the iodide compound and the organicsolvent, are charged. The reaction medium is then heated to the desiredtemperature.

The progress of the reaction is monitored by following the disappearanceof the compound carrying a leaving group. At the end of the reaction, aproduct of the type R-Q-R⁰ is obtained, wherein R, Q and R⁰ are aspreviously described.

The obtained compound is recovered using conventional techniques, inparticular by crystallization from an organic solvent.

More specific examples of organic solvents that can be used for thecrystallization step are aliphatic or aromatic, halogenated or nonhalogenated hydrocarbons, carboxamides and nitriles. Particular mentioncan be made of cyclohexane, toluene, dimethylformamide and acetonitrile.

Examples of the invention will now be given. These examples are given byway of illustration and are not limiting in nature.

Before describing the examples, we shall describe the GeneralExperimental Procedures used in all of the examples unless otherwiseindicated.

General Experimental Procedures

All reactions are carried out in 35 mL Schlenk tubes or in Carousel“reaction stations RR98030” Radley tubes, under a pure and dry nitrogenatmosphere. Dimethyl formamide (DMF) is distilled from calcium hydride(CaH₂) and is stored on 4 Å activated molecular sieves under a nitrogenatmosphere. Cesium carbonate (Acros), CuO (Acros) and Fe(acac)₃ (Acros)and all other solid materials are stored in the presence of P₄O₁₀ in abench-top desiccator under vacuum at room temperature and weighed in theair. Aryl iodide and aryl bromides are purchased from commercial sources(Aldrich, Acros, Avocado, Fluka, Lancaster).

If solids, they are re-crystallized in an appropriate solvent, forexample according to D. D. Perrin, et al., Purification of LaboratoryChemicals, 3rd ed., Pergamon Press: New-York, 1985. If liquids, they aredistilled under vacuum and stored under an atmosphere of nitrogen.Special care is taken with liquid iodobenzene which is regularlydistilled and stored protected from light.

Column chromatography is performed with SDS 60 A C.C silica gel (35-70μm). Thin layer chromatography is carried out using Merck silica gel 60F₂₅₄ plates. All products are characterized by their NMR, GC/MS and IRspectra.

NMR spectra are recorded at 20° C. on a Bruker AC 400 MHz or on aDRX-250 spectrometer working respectively at 400 MHz for ¹H, at 100 MHzfor ¹³C. Chemical shifts are reported in ppm/TMS for ¹H and {¹H}¹³C (δ77.00 for CDCl₃ signal). The first-order peak patterns are indicated ass (singlet), d (doublet), t (triplet), q (quadruplet). Complexnon-first-order signals are indicated as m (multiplet).

Gas chromatography—mass spectra (GC/MS) are recorded on an AgilentTechnologies 6890 N instrument with an Agilent 5973 N mass detector (EI)and a HP5-MS 30 m×0.25 mm capillary apolar column (Stationary phase: 5%diphenyldimethylpolysiloxane film, 0.25 μm).

GC/MS method: Initial temperature: 45° C.; Initial time: 2 min; Ramp: 2°C./min until 50° C. then 10° C./min; Final temperature: 250° C.; Finaltime: 10 min.

IR spectra are recorded on a Nicolet 210 FT-IR instrument (neat, thinfilm for liquid products and KBr pellet or in carbon tetrachloridesolution for solid products).

FAB+ mass spectra and HRMS are recorded on a JEOL JMS-DX300 spectrometer(3 keV, xenon) in a m-nitrobenzylalcohol matrix. Melting points weredetermined using a Büchi B-540 apparatus and are uncorrected.

General Procedure A: Iron-Copper Co-Catalyzed Cross-Coupling Reaction(CuO and Fe(acac)₃; 1 mmol and 2 mmol Scale)

After standard cycles of evacuation and back-filling with dry and purenitrogen, an oven-dried Radley tube (Carousel “reaction stationsRR98030”) equipped with a magnetic stirring bar is charged with CuO (0.1eq.), Fe(acac)₃ (0.3 eq.), the nucleophile (1.5 eq.), Cs₂CO₃ (2 eq.) andthe aryl halide (1 eq.), if a solid. The tube is evacuated, back-filledwith nitrogen. If a liquid, the aryl reagent is added under a stream ofnitrogen by syringe at room temperature, followed by anhydrous anddegassed DMF (1.0 mL). The tube is sealed under a positive pressure ofnitrogen, stirred and heated to 90 or 125° C. or 140° C. for therequired time period. After cooling to room temperature, the mixture isdiluted with dichloromethane (˜20 mL) and filtered through a plug ofCelite®, the filter cake being further washed with dichloromethane (˜5mL). The filtrate is washed twice with water (˜10 mL×2). Gatheredaqueous phases are twice extracted with dichloromethane (˜10 mL).Organic layers are gathered, dried over Na₂SO₄, filtered andconcentrated in vacuo to yield the crude product which is then purifiedby silica gel chromatography with an eluent of hexanes anddichloromethane. The products are characterized by NMR, IR and massspectra with those of authentic samples.

General Procedure B: Reactivity Comparison with Different CatalyticSystems (0.5 mmol Scale)

After standard cycles of evacuation and back-filling with dry and purenitrogen, an oven-dried Radley tube (Carousel “reaction stationsRR98030”) equipped with a magnetic stirring bar is charged with theindicated catalysts (see Table 1 below), the pyrazole (51 mg, 1.5 eq.)and Cs₂CO₃ (325 mg, 2 eq.). The tube is evacuated, back-filled withnitrogen. Iodobenzene (56 μL, 0.5 mmol, 1 eq.) or bromobenzene (53 μL,0.5 mmol, 1 eq.) is added under a stream of nitrogen by syringe at roomtemperature, followed by anhydrous and degassed DMF (0.5 mL). The tubeis sealed under a positive pressure of nitrogen, stirred and heated to100° C. for 15 hours. After cooling to room temperature, the mixture isdiluted with dichloromethane (˜20 mL) and filtered through a plug ofCelite®, the filter cake being further washed with dichloromethane (˜5mL). 65 μL of 1,3-dimethoxybenzene (internal standard) are added. Asmall sample of the reaction mixture is taken and filtered through aplug of Celite®, the filter cake being further washed withdichloromethane. The filtrate is washed three times with water andanalyzed by gas chromatography.

“GC (“Gas Chromatography”) yields” are determined by obtaining thecorrection factors using authentic samples of the expected products.“Isolated Yields” refer to yields after purification by columnchromatography on silica gel or alumina; all yields are based on thedefault reagent.

General Procedure C: Iron-Copper Co-Catalyzed Cross-Coupling Reaction(Cu(acac)₂ and FeCl₃; 1 mmol and 2 mmol Scale)

After standard cycles of evacuation and back-filling with dry and purenitrogen, an oven-dried Radley tube (Carousel “reaction stationsRR98030”) equipped with a magnetic stirring bar is charged withCu(acac)₂ (0.1 eq.), FeCl₃ (0.3 eq.), the nucleophile (1.5 eq.), Cs₂CO₃(2 eq.), NaI (0.5 eq.), or without NaI, and the aryl halide (1 eq.), ifa solid. The tube is evacuated, back-filled with nitrogen. If a liquid,the aryl reagent is added under a stream of nitrogen by syringe at roomtemperature, and 2,2,6,6-tetramethyl-3,5-heptanedione (0.9 eq.) isadded, followed by anhydrous and degassed DMF (1.0 mL). The tube issealed under a positive pressure of nitrogen, stirred and heated to 140°C. for the required time period. After cooling to room temperature, themixture is diluted with dichloromethane (˜20 mL) and filtered through aplug of Celite®, the filter cake being further washed withdichloromethane (˜5 mL). The filtrate is washed twice with water (˜10mL×2). Gathered aqueous phases are twice extracted with dichloromethane(˜10 mL). Organic layers are gathered, dried over Na₂SO₄, filtered andconcentrated in vacuo to yield the crude product which is then purifiedby silica gel chromatography with an eluent of hexanes anddichloromethane. The products are characterized by NMR, IR and massspectra with those of authentic samples.

Experimental Procedures and Characterization Data Example A1 Preparationof 1-phenyl-1H-pyrazole

Following General Procedure A (90° C., 30 hours), 1H-pyrazole (205 mg,3.0 mmol) is coupled with bromobenzene (212 μL, 2.0 mmol). The crudebrown oil is purified by flash chromatography on silica gel (eluent:dichloromethane/hexanes=50/50) to provide 270 mg (94% isolated yield) ofthe desired product as a light yellow oil.

Identification

¹H NMR (400 MHz, CDCl₃): δ 7.95-7.96 (dd, 1H, H₇), 7.71-7.75 (m, 3H,H_(2,6,9)), 7.47-7.50 (m, 2H, H_(3,5)), 7.28-7.34 (m, 1H, H₄), 6.49-6.50(dd, 1H, H₈).

¹³C NMR (100 MHz, CDCl₃): δ 141.09 (C₉), 140.22 (C₁), 129.45 (C_(3,5)),126.75 (C₇), 126.46 (C₄), 119.23 (C_(2,6)), 107.61 (C₈).

IR (KBr): v (cm⁻¹)=3142, 3050, 2924, 1600, 1520, 1500, 1393, 1332, 1198,1120, 1046, 936, 914, 755, 689, 654, 610, 515.

GC/MS: rt=14.53 min, M/Z=144.

HRMS: 145.0766 (M+H). Theoretical: 145.0766.

Example A2 Preparation of 1-phenyl-1H-imidazole

Following General Procedure A (90° C., 30 hours), 1H-imidazole (102 mg,1.5 mmol) is coupled with iodo-benzene (112 μL, 1.0 mmol). The crudebrown oil is purified by flash chromatography on silica gel (eluent:hexane/ethylacetate=20/80) to provide 130 mg (90% isolated yield) of thedesired product as a light yellow oil.

Identification

¹H NMR (400 MHz, CDCl₃): δ 7.81 (s, 1H, Hg), 7.40-7.43 (m, 2H, H_(3,5)),7.28-7.34 (m, 3H, H_(2,4,6)), 7.22 (s, 1H, H7), 7.15 (s, 1H, H₈).

¹³C NMR (100 MHz, CDCl₃): δ 137.35 (C₁), 135.59 (C₉), 130.32 (C₈),129.92 (C_(3,5)), 127.56 (C₄), 121.53 (C_(2,6)), 118.32 (C₇).

IR (KBr): v (cm⁻¹)=3115, 3067, 1600, 1509, 1304, 1247, 1112, 1057, 962,905, 815, 759, 692, 658, 520.

GC/MS: rt=16.16 min, M/Z=144.

HRMS: 145.0768 (M+H). Theoretical: 145.0766.

Example A3 Preparation of 4-pyrazol-1-yl benzoic acid ethyl ester

Following General Procedure A (90° C., 30 hours), 1H-pyrazole (205 mg,3.0 mmol) is coupled with ethyl 4-iodobenzoate (336 μL, 2.0 mmol). Thecrude brown oil is purified by flash chromatography on silica gel(eluent: dichloromethane/hexanes=80/20) to provide 400 mg (93% isolatedyield) of the desired product as a white solid.

Identification

Mp: 66° C.

¹H NMR (400 MHz, CDCl₃): δ 8.05-8.07 (d, 2H, H_(3,5)), 7.92-7.93 (d, 1H,H₇), 7.68-7.72 (m, 3H, H_(2,6,9)), 6.42-6.43 (t, 1H, H₈), 4.29-4.34 (q,2H, H₁₁), 1.32-1.35 (t, 3H, H₁₂).

¹³C NMR (100 MHz, CDCl₃): δ 165.90 (C₁₀), 143.20 (C₁), 141.89 (C₉),131.12 (C_(3,5)), 128.17 (C₄), 126.90 (C₇), 118.27 (C_(2,6)), 108.46(C₈), 61.13 (C₁₁), 14.35 (C₁₂).

IR (KBr): v (cm⁻¹)=3128, 2993, 2962, 2904, 1702, 1608, 1526, 1481, 1392,1341, 1280, 1201, 1178, 1111, 1048, 1027, 935, 852, 767, 692, 652, 610,525, 505, 478.

GC/MS: rt=20.94 min, M/Z=216.

HRMS: 217.0983 (M+H). Theoretical: 217.0977.

Example A4 Preparation of 1-(4-methoxyphenyl)-1H-pyrazole

Following General Procedure A (90° C., 30 hours), 1H-pyrazole (205 mg,3.0 mmol) is coupled with 1-iodo-4-methoxybenzene (468 mg, 2.0 mmol).The crude brown oil is purified by flash chromatography on silica gel(eluent: dichloromethane/hexanes=50/50) to provide 340 mg (98% isolatedyield) of the desired product as a white solid.

Identification

Mp: 42° C.

¹H NMR (400 MHz, CDCl₃): δ 7.72-7.73 (d, 1H, H₇), 7.60-7.61 (d, 1H, H₉),7.47-7.51 (m, 2H, H_(2,6)), 6.85-6.89 (m, 2H, H_(3,5)), 6.33 (s, 1H,H₈), 3.73 (s, 3H, H₁₀).

¹³C NMR (100 MHz, CDCl₃): δ 158.21 (C₄), 140.60 (C₉), 133.99 (C₁),126.84 (C₇), 120.88 (C_(2,6)), 114.50 (C_(3,5)), 107.20 (C₈), 55.56(C₁₀).

IR (KBr): v (cm⁻¹)=3124, 3003, 2936, 2913, 2836(C—O), 1594, 1522, 1464,1444, 1396, 1246, 1171, 1039, 938, 831, 750, 617, 531.

GC/MS: rt=17.99 min, M/Z=174.

HRMS: 175.0872 (M+H). Theoretical: 175.0871.

Example A5 Preparation of 1-biphenyl-4-yl-1H-pyrazole

Following general procedure A (90° C., 30 hours), 1H-pyrazole (205 mg,3.0 mmol) is coupled with 4-bromo-1,1′-biphenyl (446 mg, 2.0 mmol). Thecrude brown oil is purified by flash chromatography on silica gel(eluent: dichloromethane/hexanes=50/50) to provide 410 mg (93% isolatedyield) of the desired product as a white crystal.

Identification

Mp: 134° C.

¹H NMR (400 MHz, CDCl₃): δ 7.88 (s, 1H, H₇), 7.67-7.70 (m, 3H,H_(3,5,9)), 7.59-7.61 (m, 2H, H_(11,15)), 7.52-7.55 (m, 2H, H_(2,6)),7.36-7.39 (m, 2H, H_(12,14)), 7.26-7.30 (m, 1H, H₁₃), 6.40-6.41 (t, 1H,H₈).

¹³C NMR (100 MHz, CDCl₃): δ 141.20 (C₉), 140.11 (C₁), 139.33 (C_(4,10)),128.91 (C_(12,14)), 128.08 (C_(3,5)), 127.52 (C₇), 126.99 (C_(11,15)),126.71 (C₁₃), 119.45 (C_(2,6)), 107.73 (C₈).

IR (KBr): v (cm⁻¹)=3129, 3106, 3026, 1607, 1529, 1484, 1393, 1331, 1050,938, 835, 763, 699, 553, 516.

GC/MS: rt=23.60 min, M/Z=220.

HRMS: 221, 1068 (M+H). Theoretical: 221.1079.

Example A6 Preparation of 4-pyrazol-1-yl-benzonitrile

Following General Procedure A (90° C., 30 hours), 1H-pyrazole (205 mg,3.0 mmol) is coupled with 4-bromobenzonitrile (364 mg, 2.0 mmol). Thecrude brown oil is purified by flash chromatography on silica gel(eluent: dichloromethane/hexanes=50/50) to provide 330 mg (98% isolatedyield) of the desired product as a white solid.

Identification

Mp: 89° C.

¹H NMR (400 MHz, CDCl₃): δ 7.92-7.93 (d, 1H, H₇), 7.75-7.78 (m, 2H,H_(3,5)), 7.65-7.70 (m, 3H, H_(2,6,9)), 6.46-6.47 (dd, 1H, H₈).

¹³C NMR (100 MHz, CDCl₃): δ 142.95 (C₁), 142.50 (C₉), 133.68 (C_(3,5)),126.94 (C₇), 118.93 (C_(2,6)), 118.44 (C₁₀), 109.53 (C₄), 109.15 (C₈).

IR (KBr): v (cm⁻¹)=3153, 3136, 3066, 2226(CN), 1610, 1528, 1513, 1392,1342, 1252, 1199, 1176, 1127, 1030, 934, 834, 813, 749, 650, 572, 545.

GC/MS: rt=18.92 min, M/Z=169.

HRMS: 170.0700 (M+H). Theoretical: 170.0718.

Example A7 Preparation of 1-(4-pyrazol-1-yl-phenyl)ethanone

Following General Procedure A (90° C., 30 hours), 1H-pyrazole (205 mg,3.0 mmol) is coupled with 1-(4-bromophenyl)ethanone (398 mg, 2.0 mmol).The crude brown oil is purified by flash chromatography on silica gel(eluent: dichloromethane/hexanes=50/50) to provide 300 mg (81% isolatedyield) of the desired product as a white solid.

Identification

Mp: 108° C.

¹H NMR (400 MHz, CDCl₃): δ 7.98-8.00 (m, 3H, H_(3,5,7)), 7.70-7.76 (m,3H, H_(2,6,9)), 6.46 (s, 1H, H₈), 2.56 (s, 3H, H₁₁).

¹³C NMR (100 MHz, CDCl₃): δ 196.84 (C₁₀), 143.33 (C₁), 142.09 (C₉),134.80 (C₄), 130.01 (C_(3,5)), 126.91 (C₇), 118.39 (C_(2,6)), 108.62(C₈), 26.60 (C₁₁).

IR (KBr): v (cm⁻¹)=3135, 3114, 3101, 1673(C═O), 1605, 1528, 1395, 1264,1210, 935, 838, 762, 611, 589, 518.

GC/MS: rt=19.96 min, M/Z=186.

HRMS: 187.0893 (M+H). Theoretical: 187.0871.

Example A8 Preparation of 1-(4-nitro-phenyl)-1H-pyrazole

Following General Procedure A (90° C., 30 hours), 1H-pyrazole (205 mg,3.0 mmol) is coupled with 1-bromo-4-nitrobenzene (404 mg, 2.0 mmol). Thecrude brown oil is purified by flash chromatography on silica gel(eluent: dichloromethane/hexanes=50/50) to provide 340 mg (90% isolatedyield) of the desired product as a yellow solid.

Identification

Mp: 170° C.

¹H NMR (400 MHz, CDCl₃): δ 8.26-8.29 (m, 2H, H_(3,5)), 7.97 (d, 1H, H₇),7.81-7.84 (m, 2H, H_(2,6)), 7.73-7.74 (d, 1H, Hg), 6.49-6.50 (dd, 1H,H₈).

¹³C NMR (100 MHz, CDCl₃): δ 144.42 (C₄), 142.81 (C₉), 133.52 (C₁),134.80 (C₄), 127.08 (C₇), 125.42 (C_(3,5)), 118.62 (C_(2,6)), 109.38(C₈).

IR (KBr): v (cm⁻¹)=3152, 3119, 3085, 1596, 1532, 1517, 1392, 1334(NO₂),1206, 1112, 1050, 1030, 929, 852, 764, 749, 685, 497.

GC/MS: rt=20.30 min, M/Z=189.

HRMS: 190.0615 (M+H). Theoretical: 190.0617.

Example A9 Preparation of 1-(4-tolyl)-1H-pyrazole

Following General Procedure A (125° C., 24 hours), 1H-pyrazole (102 mg,1.5 mmol) is coupled with 1-bromo-4-methylbenzene (122 μL, 1.0 mmol).The crude brown oil is purified by flash chromatography on silica gel(eluent: dichloromethane/hexanes=70/30) to provide 90 mg (57% isolatedyield) of the desired product as an uncolored oil.

Identification

¹H NMR (400 MHz, CDCl₃): δ 7.78-7.79 (m, 1H, H₇), 7.62 (d, 1H, H₉),7.47-7.49 (d, 2H, H_(2,6)), 7.14-7.17 (t, 2H, H_(3,5)), 6.35-6.36 (dd,1H, H₈), 2.29 (s, 3H, H₁₀).

¹³C NMR (100 MHz, CDCl₃): δ 139.72 (C₉), 136.95 (C₁), 135.18 (C₄),128.88 (C_(3,5)), 125.63 (C₇), 118.13 (C_(2,6)), 106.27 (C₈), 19.87(C₁₀).

IR (KBr): v (cm⁻¹)=3123, 3040, 2922, 2863, 1610, 1525, 1394, 1331, 1196,1123, 1046, 1031, 937, 915, 815, 749, 615, 518.

GC/MS: rt=16.08 min, M/Z=158.

HRMS: 159.0913 (M+H). Theoretical: 159.0922.

Example A10 Preparation of 1-(4-trifluoromethyl-phenyl)-1H-pyrazole

Following General Procedure A (140° C., 24 hours), 1H-pyrazole (102 mg,1.5 mmol) is coupled with 1-chloro-4-(trifluoromethyl)benzene (134 μL,1.0 mmol). The crude brown oil is purified by flash chromatography onsilica gel (eluent: dichloromethane/hexanes=50/50) to provide 80 mg (38%isolated yield) of the desired product as a white solid.

Identification

Mp: 93° C.

¹H NMR (400 MHz, CDCl₃): δ 7.92-7.93 (d, 1H, H₇), 7.76-7.78 (d, 2H,H_(3,5)), 7.70 (d, 1H, Hg), 7.64-7.66 (d, 2H, H_(2,6)), 6.45-6.46 (dd,1H, H₈).

¹³C NMR (100 MHz, CDCl₃): δ 142.53 (C₁), 141.96 (C₉), 126.81 (C₇),126.74 (m, C_(3,5)), 125.29 (C₄), 122.59 (C₁₀), 118.81 (C_(2,6)), 108.53(C₈).

IR (KBr): v (cm⁻¹)=3152, 3136, 2964, 2925, 1619, 1532, 1414, 1394, 1334,1123, 1106, 1071, 935, 852, 824, 756, 605, 591.

GC/MS: rt=14.54 min, M/Z=212.

HRMS: 213.0659 (M+H). Theoretical:213.0640

Example A11 Preparation of 4-(1H-pyrazol-1-yl)aniline

Following General Procedure A (125° C., 24 hours), 1H-pyrazole (102 mg,1.5 mmol) is coupled with 4-iodoaniline (220 mg, 1.0 mmol). The crudebrown oil is purified by flash chromatography on silica gel (eluent:dichloromethane/hexanes=50/50) to provide 90 mg (57% isolated yield) ofthe desired product as an orange solid.

Identification

Mp: 42° C.

¹H NMR (400 MHz, CDCl₃): δ 7.70 (dd, 1H, H₇), 7.59 (d, 1H, Hg),7.34-7.38 (m, 2H, H_(2,6)), 6.63-6.67 (m, 2H, H_(3,5)), 6.33-6.34 (m,1H, H₈), 3.67 (s, 2H, H₁₀).

¹³C NMR (100 MHz, CDCl₃): δ 145.33 (C₄), 140.24 (C₉), 132.39 (C₁),126.76 (C₇), 121.11 (C_(2,6)), 115.46 (C_(3,5)), 106.83 (C₈).

IR (KBr): v (cm⁻¹)=3381, 3298, 3192, 1632, 1525, 1398, 1280, 1176, 1126,1051, 1033, 943, 823, 751, 612, 521.

GC/MS: rt=19.16 min, M/Z=159.

HRMS: 160.0873 (M+H). Theoretical: 160.0875.

Example A12 Preparation of 1-(3-methoxy-phenyl)-1H-pyrazole

Following General Procedure A (125° C., 24 hours), 1H-pyrazole (102 mg,1.5 mmol) is coupled with 1-bromo-3-methoxybenzene (126 μL, 1.0 mmol).The crude brown oil is purified by flash chromatography on silica gel(eluent: dichloromethane/hexanes=40/60) to provide 150 mg (86% isolatedyield) of the desired product as an uncolored oil.

Identification

¹H NMR (400 MHz, CDCl₃): δ 7.79 (d, 1H, H₇), 7.61 (d, 1H, Hg), 7.19-7.23(m, 2H, H_(4,6)), 7.11-7.12 (m, 1H, H₃), 6.69-6.72 (dd, 1H, H₂),6.32-6.33 (dd, 1H, H₈), 3.73 (s, 3H, H₁₀).

¹³C NMR (100 MHz, CDCl₃): δ 160.54 (C₅), 141.33 (C₁), 141.03 (C₉),130.18 (C₃), 126.92 (C₇), 112.35 (C₄), 111.10 (C₂), 107.63 (C₈), 105.05(C₆), 55.47 (C₁₀).

IR (KBr): v (cm⁻¹)=3143, 3003, 2960, 2938, 2836(C—O), 1608, 1519, 1502,1439, 1393, 1338, 1313, 1296, 1270, 1227, 1116, 1046, 947, 844, 751,686, 656, 623, 569.

GC/MS: rt=17.77 min, M/Z=174.

HRMS: 175.0870 (M+H). Theoretical: 175.0871.

Example A13 Preparation of 1-phenyl-pyrrolidin-2-one

Following General Procedure A (90° C., 30 hours), pyrrolidin-2-one (116μL, 1.5 mmol) is coupled with iodo-benzene (112 μL, 1.0 mmol). The crudebrown oil is purified by flash chromatography on silica gel (eluent:dichloromethane/ethylacetate=80/20) to provide 130 mg (81% isolatedyield) of the desired product as a yellow solid.

Identification

Mp: 68° C.

¹H NMR (400 MHz, CDCl₃): δ 7.53-7.55 (m, 2H, H_(3,5)), 7.28-7.32 (dd,2H, H_(2,6)), 7.08 (s, 1H, H₄), 3.78-3.82 (t, 2H, H₇), 2.53-2.57 (t, 2H,H₉), 2.08-2.12 (m, 2H, H₈).

¹³C NMR (100 MHz, CDCl₃): δ 174.22 (C₁₀), 139.42 (C₁), 128.84 (C_(3,5)),124.51 (C₄), 119.97 (C_(2,6)), 48.80 (C₇), 32.79 (C₉), 18.06 (C₈).

IR (KBr): v (cm⁻¹)=3001, 2968, 2898, 1681, 1596, 1499, 1463, 1401, 1307,1229, 1117, 905, 842, 765, 695, 660, 637, 546, 504.

GC/MS: rt=18.72 min, M/Z=161.

HRMS: 162.0911 (M+H). Theoretical: 162.0919.

Example A14 Preparation of 1-phenyl-1H-[1,2,4]triazole

Following General Procedure A (90° C., 30 hours), 1H-[1,2,4]triazole(104 mg, 1.5 mmol) is coupled with iodo-benzene (112 μL, 1.0 mmol). Thecrude brown oil is purified by flash chromatography on silica gel(eluent: dichloromethane/hexanes=50/50) to provide 120 mg (83% isolatedyield) of the desired product as a light yellow solid.

Identification

Mp: 46° C.

¹H NMR (400 MHz, CDCl₃): δ 8.49 (s, 1H, H₈), 8.03 (s, 1H, H₇), 7.58-7.61(m, 2H, H_(2,6)), 7.40-7.44 (t, 2H, H_(3,5)), 7.31-7.33 (t, 1H, H₄).

¹³C NMR (100 MHz, CDCl₃): δ 152.62 (C₇), 140.91 (C₈), 136.99 (C₁),129.77 (C_(3,5)), 128.21 (C₄), 120.04 (C_(2,6)).

IR (KBr): v (cm⁻¹)=3105, 2924, 2852, 1600, 1514, 1416, 1359, 1278, 1223,1152, 1055, 981, 876, 754, 681, 671, 503.

GC/MS: rt=15.28 min, M/Z=145.

HRMS: 146.0721 (M+H). Theoretical: 146.0718.

Example A15 Preparation of 2-phenyl-2H-[1,2,3]triazole and1-phenyl-1H-[1,2,3]triazole

Following General Procedure A (90° C., 30 hours), 1H-[1,2,3]triazole (87μL, 1.5 mmol) is coupled with iodo-benzene (112 μL, 1.0 mmol). The crudebrown oil was purified by flash chromatography on silica gel (eluent:dichloromethane/hexanes=50/50 then pure dichloro-methane) to provide 60mg of 2-phenyl-2H-[1,2,3]triazole (41% yield) as an uncolored oil and 70mg of 1-phenyl-1H-[1,2,3]triazole (48% isolated yield) as a light yellowsolid.

Identification

¹H NMR (400 MHz, CDCl₃): δ 7.99-8.02 (m, 2H, H_(7,8)), 7.72 (s, 2H,H_(2,6)), 7.38-7.42 (m, 2H, H_(3,5)), 7.24-7.28 (m, 1H, H₄).

¹³C NMR (100 MHz, CDCl₃): δ 139.90 (C₁), 135.51 (C₇₋₈), 129.30(C_(3,5)), 127.56 (C₄), 118.97 (C_(2,6)).

IR (KBr): v (cm⁻¹)=3125, 3060, 2926, 2854, 1598, 1500, 1410, 1376, 1260,1215, 1149, 1069, 950, 821, 756, 695, 669, 509, 457.

GC/MS: rt=13.50 min, M/Z=145.

HRMS: 146.0721 (M+H). Theoretical: 146.0718.

Mp: 56° C.

¹H NMR (400 MHz, CDCl₃): δ 7.94 (d, 1H, H₈), 7.78 (d, 1H, H₇), 7.66-7.69(m, 2H, H_(2,6)), 7.44-7.48 (m, 2H, H_(3,5)), 7.35-7.40 (m, 1H, H₄).

¹³C NMR (100 MHz, CDCl₃): δ 137.06 (C₁), 134.54 (C₇), 129.79 (C₈),128.80 (C_(3,5)), 121.78 (C₄), 120.70 (C₂₋₆).

IR (KBr): v (cm⁻¹)=3147, 3130, 3065, 1596, 1503, 1463, 1319, 1229, 1176,1092, 1038, 982, 910, 793, 762, 684, 640, 509, 440.

GC/MS: rt=16.58 min, M/Z=145.

HRMS: 146.0719 (M+H). Theoretical: 146.0718.

Example A16 Preparation of 1-phenyl-1H-pyrrole

Following General Procedure A (90° C., 30 hours), 1H-pyrrole (104 μL,1.5 mmol) is coupled with iodo-benzene (112 μL, 1.0 mmol). The crudebrown oil is purified by flash chromatography on silica gel (eluent:hexanes) to provide 130 mg (91% isolated yield) of the desired productas a white solid.

Identification

Mp: 60° C.

¹H NMR (400 MHz, CDCl₃): δ 7.28-7.34 (m, 4H, H_(2,3,5,6)), 7.14-7.15 (t,1H, H₄), 6.99-7.00 (t, 2H, H_(7,10)), 6.26-6.27 (t, 2H, H_(8,9)).

¹³C NMR (100 MHz, CDCl₃): δ 140.82 (C₁), 129.60 (C_(3,5)), 125.66 (C₄),120.57 (C_(2,6)), 119.37 (C₇₋₁₀), 110.46 (C_(8,9)).

IR (KBr): v (cm⁻¹)=3142, 3102, 2924, 1603, 1556, 1511, 1459, 1400, 1326,1255, 1189, 1083, 1014, 919, 895, 758, 719, 608, 509.

GC/MS: rt=14.09 min, M/Z=143.

HRMS: 143.0740 (M). Theoretical: 143.0735.

Example A17 Preparation of 1-phenyl-1H-indole

Following General Procedure A (90° C., 30 hours), 1H-indole (176 mg, 1.5mmol) is coupled with iodo-benzene (112 μL, 1.0 mmol). The crude brownoil is purified by flash chromatography on silica gel (eluent: hexanes)to provide 180 mg (93% isolated yield) of the desired product as a lightgreen oil.

Identification

¹H NMR (400 MHz, CDCl₃): δ 7.57-7.59 (m, 1H, H₁₁), 7.44-7.47 (m, 1H,H₈), 7.36-7.37 (d, 4H, H_(2,3,5,6)), 7.20-7.23 (m, 2H, H_(4,14)),7.04-7.12 (m, 2H, H_(9,10)), 6.56-6.57 (m, 1H, H₁₃).

¹³C NMR (100 MHz, CDCl₃): δ 139.93 (C₁), 135.95 (C₇), 129.72 (C_(2,6)),129.45 (C₁₂), 128.06 (C₁₄), 126.54 (C₄), 124.46 (C_(3,5)), 122.48 (C₉),121.26 (C₁₁), 120.49 (C₁₀), 110.64 (C₈), 103.70 (C₁₃).

IR (KBr): v (cm⁻¹)=3104, 3055, 3032, 2924, 1597, 1515, 1497, 1456, 1331,1233, 1213, 1135, 1014, 908, 773, 741, 695, 577, 426.

GC/MS: rt=20.44 min, M/Z=193.

HRMS: 193.0924 (M+H). Theoretical: 193.0891.

Example A18 Preparation of N-(diphenylmethylene)aniline

Following General Procedure A (90° C., 30 hours),1,1-diphenyl-methanimine (272 mg, 1.5 mmol) is coupled with iodo-benzene(112 μL, 1.0 mmol) to give 94% N-(diphenylmethylene)aniline.

Identification

GC/MS: rt=23.95 min, M/Z=257.

Example A19 Preparation of 1,3-dimethyl-5-phenoxybenzene

Following General Procedure A (90° C., 30 hours), 3,5-dimethyl phenol(183 mg, 1.5 mmol) is coupled with bromo-benzene (106 μL, 1.0 mmol) togive 98% 1,3-dimethyl-5-phenoxybenzene.

Identification

GC/MS: rt=18.25 min, M/Z=198.

Example A20 Preparation of diethylphenylmalonate

Following General Procedure A (90° C., 30 hours), diethyl malonate (240mg, 1.5 mmol) is coupled with iodobenzene (112 μL, 1.0 mmol) to give 90%diethylphenylmalonate.

Identification

GC/MS: rt=18.02 min, M/Z=236.

Example A21 Preparation of 1,1′-ethyne-1,2-diyldibenzene

Following General Procedure A (120° C., 30 hours), phenyl acetylene (84μL, 1.5 mmol) is coupled with iodo-benzene (112 μL, 1.0 mmol) to give95% yield 1,1′-ethyne-1,2-diyldibenzene.

Identification

GC/MS: rt=19.03 min, M/Z=178.

Example A22 Preparation of 1-(4-methoxyphenyl)-1H-pyrazole

Following General Procedure A (125° C., 24 hours), 1H-pyrazole (102 mg,1.5 mmol) is coupled with 4-methoxybromobenzene (1.0 mmol). The crudeproduct is purified by flash chromatography on silica gel to provide thedesired product (80% GC yield).

Identification

The results of the study of the reactivity comparison with variouscatalytic systems according to General Procedure B are presented inTable 1 below:

TABLE 1 Cross-coupling of benzene halide and pyrazole when usingdifferent catalytic systems. Example X [Fe] 0.3 eq. [Cu] 0.1 eq. GCYield (%) B1 Br Fe(acac)₃ Cu 83 B2 Br Fe(acac)₃ CuI 79 B3 Br Fe(acac)₃CuO 94 B4 Br Fe(acac)₃ Cu(acac)₂ 71 B5 Br Fe(acac)₃ — 0 B6 Br — CuI 0 B7Br — Cu(acac)₂ 0 B8 I Fe(acac)₃ Cu 100 B9 I Fe(acac)₃ Cu(acac)₂ 100 B10I — Cu 0 B11 I — CuI 0 B12 I — Cu(acac)₂ 0 B13 I — CuI + Cu(acac)₂ 4 B14I Fe(acac)₃ — 0

The above results clearly demonstrate that without copper the yields ofreaction are nearly null (Examples B5, B14). The blank experiments(Examples B6-B7, B10-B13) verified that without iron, there is noconversion either.

The process of the present invention allows cross-coupling reactionsbetween a nucleophilic compound and a compound carrying a leaving group,using a catalytic system comprising an iron-based catalyst inassociation with a copper-based catalyst. Both catalysts are both notexpensive and easy to handle. The reactions are run under mildconditions and a large scope of substituants (nucleophilic compounds andcompounds carrying a leaving group) are tolerated, with a goodselectivity, i.e. fairly no to no side-reaction products.

It is indeed remarkable that there are no obvious side reactions, so thetreatments can be much simplified.

Example C1 Preparation of1,3-dimethyl-5-(3′-trifluoromethylphenoxy)-benzene

Following General Procedure C (140° C., 30 hours), 3,5-dimethylhenol(183 mg, 1.5 mmol) is coupled with 1-chloro-3-(trifluoromethyl)benzene(146 μL, 1.0 mmol) to give 97% 1,3-dimethyl-5-(3′-trifluoromethylphenoxy)benzene.

Identification

GC/MS: rt=44.27 min, M/Z=266.

Example C2 Preparation of 1,3-dimethyl-5-phenoxybenzene

Following General Procedure C (140° C., 30 hours), 3,5-dimethyl-phenol(183 mg, 1.5 mmol) is coupled with chlorobenzene (102 μL, 1.0 mmol) togive 60% 1,3-dimethyl-5-phenoxybenzene.

Identification

GC/MS: rt=18.25 min, M/Z=198.

Example C3 Preparation of 1,1′-ethyne-1,2-diyldibenzene

Following General Procedure C (120° C., 30 hours), phenylacetylene (84μL, 1.5 mmol) was coupled with bromobenzene (106 μL, 1.0 mmol), in thepresence of sodium iodide (NaI; 0.5 eq.; 0.5 mmol). The crude brown oilwas purified by flash chromatography on silica gel to provide 90%1,1′-ethyne-1,2-diyldibenzene.

Identification

GC/MS: rt=19.03 min, M/Z=178.

The invention claimed is:
 1. A process for creating a compound offormula (III):

the process comprising: reacting, in the presence of an effectivequantity of a catalytic system comprising iron and copper, a compound offormula (IIc):

wherein in formula (IIc): E represents a residue of a cycle compound,containing 4, 5 or 6 carbon atoms in its cycle, optionally substituted,and representing at least one of the following cycles: a monocyclic orpolycyclic aromatic carbocycle, the polycyclic aromatic carbocycleselected from the group consisting of a compound constituted by at least2 aromatic carbocycles and between them forming ortho- or ortho- andperi-condensed systems, and a compound constituted by at least 2carbocycles only one of which is aromatic and between them formingortho- or ortho- and peri-condensed systems; or a monocyclic aromaticheterocycle having at least one of heteroatoms P, O, N or S, or apolycyclic aromatic heterocycle, selected from the group consisting of acompound constituted by at least 2 heterocycles having at least oneheteroatom in each cycle wherein at least one of the two cycles isaromatic and bet ween them forming ortho- or ortho- and peri-condensedsystems, and a compound constituted by at least one carbocycle and atlead one heterocycle at least one of the cycles being aromatic and forbetween them ortho- or ortho- and peri-condensed systems; R³⁷, which maybe identical or different, represents substituents on the cycle; Yrepresents a halogen atom or a group of formula —OSO₂—R^(e), in whichR^(e) is a hydrocarbon group; and n″ represents the number ofsubstituents on the cycle and is 0, 1, 2, 3, 4 or 5, with a nucleophiliccompound of formula (Ik):

wherein in formula (Ik): A represents the residue of a cycle forming allor a portion of a monocyclic or polycyclic, aromatic or non aromaticheterocyclic system, wherein one of the carbon atoms is replaced by atleast one nucleophilic atom selected from the group consisting of anitrogen, sulfur and phosphorus atom; R²² represents C1-C6 alkyl, C2-C6alkenyl or alkynyl, C1-C6 alkoxy or thioether, cyclohexyl, phenyl,benzyl, a group or function such as hydroxyl, thiol, carboxyl, ester,amide, formyl, acyl, aroyl, amide, urea, isocyanate, thioisocyanate,nitrile, azide, nitro, sulfone, sulfonic, halogen, pseudo-halogen ortrifluoromethyl; and n represents the number of substituents on thecycle and is 0, 1, 2, 3 or
 4. 2. The process according to claim 1,wherein A represents one of the following cycles: a monocyclicheterocycle containing one or more heteroatoms, selected from the groupconsisting of:

a bicycle comprising a carbocycle and a heterocycle comprising one ormore heteroatoms, selected from the group consisting of:

or a tricycle comprising at least one carbocycle or a heterocyclecomprising one or more heteroatoms, selected from the group consistingof:


3. The process according to claim 1, wherein A represents imidazole,pyrazole, triazole, pyrazine, oxadiazole, oxazole, tetrazole, indole,pyrrole, phthalazine, pyridazine or oxazolidine.
 4. The processaccording to claim 1, wherein the ratio between the number of moles ofthe compound of formula (IIc) and the number of moles of the compound offormula (Ik) is in the range of 0.1 to 2.0.
 5. The process according toclaim 1, wherein the catalytic system comprises an iron-based catalyst,in association with a copper-based catalyst, said iron-based catalystbeing selected from the group consisting of metallic iron, oxides ofiron(II) or iron(III), hydroxides of iron(II) or iron(III), organic orinorganic salts of iron(II) or iron(III), and iron(II) or iron(III)complexes with common usual ligands.
 6. The process according to claim5, wherein said iron-based catalyst is selected from the groupconsisting of iron(0), iron halides, iron nitrates, iron perchloratesand iron organic salts in which the counter anion involves at least onecarbon atom.
 7. The process according to claim 1, wherein the catalyticsystem comprises an iron-based catalyst, in association with acopper-based catalyst, said copper-based catalyst selected from thegroup consisting of metallic copper, oxides of copper(I) or copper(II),hydroxides of copper(I) or copper(II), organic or inorganic salts ofcopper(I) or copper(II), and copper(I) or copper(II) complexes withcommon usual ligands.
 8. The process according to claim 7, wherein saidcopper-based catalyst is chosen from among copper(0), copper halides,copper oxides or hydroxides, copper nitrates, copper sulfates, coppersulfites, and copper organic salts in which the counter anion involvesat least one carbon atom.
 9. The process according to claim 1, whereinthe catalytic system comprises Fe(acac)₃ together with a copper-basedcatalyst selected from the group consisting of Cu(0), CuI, CuO,Cu(acac)₂, and mixtures thereof.
 10. The process according to claim 5,wherein the iron-based catalyst/copper-based catalyst molar ratio(expressed as [number of moles of Fe/number of moles of Cu]) is in therange 10/1 to 1/10.
 11. The process according to claim 1, wherein atotal amount of catalyst ([Fe]+[Cu]), expressed as a molar ratio between(number of moles of Fe+number of moles of Cu) and a number of moles ofthe compound of formula (IIc), is in the range of 0.001 to 0.5.
 12. Theprocess according to claim 1, wherein the reaction is further carriedout in the presence of a base.
 13. The process according to claim 12,wherein a pKa of the base is greater than about
 2. 14. The processaccording to claim 12, wherein the base is selected from the groupconsisting of alkali metal carbonates, bicarbonates, phosphates orhydroxides; alkali metal hydrides; and tertiary amines.
 15. The processaccording to claim 12, wherein the compound carrying the leaving groupis an aromatic compound and a quantity of base employed is such that aratio between the number of moles of base and the number of moles of thecompound of formula (IIc) is in the range 1 to
 4. 16. The processaccording to claim 1, wherein the reaction is further carried out in thepresence of a solvent.
 17. The process according to claim 16, whereinthe solvent is a polar organic solvent.
 18. The process according toclaim 16, wherein the solvent is selected from the group consisting of:linear or cyclic carboxamides; dimethylsulfoxide (DMSO);hexamethylphosphotriamide (HMPT); tetramethyurea; nitro compounds andnitrobenzene; aliphatic or aromatic nitriles; tetramethylene sulfone(sulfolane); organic carbonates; alkyl esters; halogenated or nonhalogenated aromatic hydrocarbons; ketones; and nitrogen-containingheterocycles.
 19. The process according to claim 16, wherein thequantity of solvent is such that the concentration of the compound offormula (IIc) in the solvent is in the range 5% to 40% by weight. 20.The process according to claim 1, wherein the reaction is conducted at atemperature in the range 0° C. to 200° C.
 21. The process according toclaim 1, further comprising the steps of: charging the catalytic system,the compound of formula (Ik), a base, the compound of formula (IIc),optionally an iodide compound, and optionally a solvent; heating thereaction medium to a desired temperature; and recovering thecross-coupling reaction product.
 22. The process according to claim 1,wherein the reaction takes place in the presence of an effectivequantity of a catalytic system comprising iron, together with a catalystselected from the group consisting of Cu(0), CuI, CuO, Cu(acac)₂, andmixtures thereof, in the presence of a base.
 23. The process accordingto claim 1, wherein the reaction is run in a carboxamide-type solvent,at a temperature in the range 0° C. to 200° C.
 24. The process accordingto claim 4, wherein the ratio between the number of moles of thecompound of formula (IIc) and the number of moles of the compound offormula (Ik) is in the range of 0.5 and 1.5.
 25. The process accordingto claim 4, wherein the ratio between the number of moles of thecompound of formula (IIc) and the number of moles of the compound offormula (Ik) is in the range of 0.8 and 1.2.
 26. The process accordingto claim 4, wherein the ratio between the number of moles of thecompound of formula (IIc) and the number of moles of the compound offormula (Ik) is in the range of 0.9 and 1.1.
 27. The process accordingto claim 10, wherein the iron-based catalyst/copper-based catalyst molarratio (expressed as [number of moles of Fe/number of moles of Cu]) is inthe range 10/1 to 1/1.
 28. The process according to claim 10, whereinthe iron-based catalyst/copper-based catalyst molar ratio (expressed as[number of moles of Fe/number of moles of Cu]) is in the range 5/1 to1/1.
 29. The process according to claim 10, wherein the iron-basedcatalyst/copper-based catalyst molar ratio (expressed as [number ofmoles of Fe/number of moles of Cu]) is 3/1.
 30. The process according toclaim 11, wherein the total amount of catalyst ([Fe]+[Cu]), expressed asthe molar ratio between (number of moles of Fe+number of moles of Cu)and the number of moles of the compound of formula (IIc), is in therange of 0.01 to 0.1.
 31. The process according to claim 13, wherein thepKa of the base is in the range of 4 to
 30. 32. The process according toclaim 17, wherein the solvent is an aprotic polar organic solvent. 33.The process according to claim 20, wherein the reaction is conducted ata temperature in the range of 20° C. to 170° C.
 34. The processaccording to claim 20, wherein the reaction is conducted at atemperature in the range of 25° C. to 140° C.
 35. The process accordingto claim 1, wherein A represents imidazole, pyrazole, triazole, indole,pyrrole, pyrrolidine, or pyrrolidone.
 36. The process of claim 1,wherein E represents a benzene ring.